# NM_001354640.2(CIROP):c.2159+2T>A

https://sugi.bio/variant/cirop-c-2159-plus-2t-a

## Summary

**CIROP c.2159+2T>A** is classified **Uncertain significance** in CIROP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Rare (popmax 0.124%, mid); Associated with trichothiodystrophy 1, photosensitive.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · rare (popmax 0.124%, mid)

## For patients & families {#patients}

This is a change in the CIROP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to trichothiodystrophy 1, photosensitive.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Diagnostic panels | CIROP is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005270/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CIROP](https://sugi.bio/atlas/gene/CIROP/) |
| Coding change (HGVS c.) | c.2159+2T>A |
| MANE Select transcript | [NM_001354640](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354640) |
| Variant type | single nucleotide variant |
| Location | chr14:23100500-23100500 (GRCh38) |
| ClinVar | [VCV4277730](https://www.ncbi.nlm.nih.gov/clinvar/variation/4277730/) |

**All HGVS expressions:** `NC_000014.8:g.23569709A>T`, `NC_000014.9:g.23100500A>T`, `NG_030461.1:g.115T>A`, `NG_030461.2:g.114T>A`, `NM_001354640.2:c.2159+2T>A`, `NM_001402427.1:c.1994+2T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 8.684, GERP 2.22, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **canonical splice-site (±1/±2)** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 24.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **canonical splice dinucleotide (donor +2)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 0.54**, o/e 0.96 (1 kb window 23,100,000–23,101,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Pangolin: Δ**0.37** (loss), gain 0.02 / loss 0.37. Not in the SpliceAI release. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.124%** (mid) · FAF95 0.022% · FAF99 0.00915% · 2/1,612 in the highest group · 25/413,362 alleles overall — rare (popmax 0.124%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.124% | 806 |
| Remaining individuals (not grpmax-eligible) | 0.0108% | 9,278 |
| Admixed American | 0.0088% | 11,362 |
| European (non-Finnish) | 0.0084% | 11,903 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.73, 35% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[trichothiodystrophy 1, photosensitive](https://sugi.bio/atlas/disease/trichothiodystrophy-1-photosensitive/).

**Reported phenotype names (ClinVar):** Trichothiodystrophy 1, photosensitive, TAY SYNDROME, TRICHOTHIODYSTROPHY WITH CONGENITAL ICHTHYOSIS, PIBIDS SYNDROME.

## Similar variants {#similar}

Related CIROP variant pages (same residue, condition, or type): [CIROP c.988+1G>C](/variant/cirop-c-988-plus-1g-c), [CIROP p.Glu376Lys](/variant/cirop-p-glu376lys), [CIROP p.Gln528Ter](/variant/cirop-p-gln528ter), [CIROP p.Arg22Ter](/variant/cirop-p-arg22ter), [CIROP p.Gly180Arg](/variant/cirop-p-gly180arg), [CIROP p.Gly511Glu](/variant/cirop-p-gly511glu), [CIROP p.Ser31Phe](/variant/cirop-p-ser31phe), [CIROP p.Tyr68Cys](/variant/cirop-p-tyr68cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4277730). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*