chr2-203866221-T-C

Variant names:

• chr2-203866221-T-C
• rs733618
• ENST00000696479.1:c.48-1697T>C

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_Strong

The ENST00000696479.1(CTLA4):c.48-1697T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000696479.1 is not a MANE Select or MANE Plus Clinical transcript for CTLA4; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The gene CTLA4 is a known oncogene (CancerMine: 9 oncogene, 1 driver citations). The gene CTLA4 is a cancer driver gene (CancerMine: 9 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.105 (AC=15,976) in the gnomAD database across 152,230 control chromosomes, including 1,131 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.379. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1131 hom., cov: 32)
• Consequence: CTLA4 ENST00000696479.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 1 publications found

Genes affected

CTLA4 (HGNC:2505): (cytotoxic T-lymphocyte associated protein 4) This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]

CTLA4 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for CTLA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.379 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000696479.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CTLA4 ENST00000696479.1		c.48-1697T>C	intron	Intron 1 of 4	Prot: ENSP00000512655.1 UniProt:

CTLA4 ENST00000696479.1

HGVSc / HGVSpc.48-1697T>C

Exon rankIntron 1 of 4

intron

Prot: ENSP00000512655.1UniProt: A0A8Q3SIR7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.105	AC:15961	Hom:1129	AN:152114	Cov:32
GnomAD4 genome	AF: 0.105	AC:15976	Hom:1131	AN:152230	Cov:32
TOPMed (Bravo)	AF: 0.110	AC:29122	Hom:2215	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0912	AC:46566	Hom:2785	AN:510332	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0781	AC:183	Hom:14	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.389	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0433	AC:13	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.226	AC:784	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.423	AC:3063	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0795	AC:14	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.410	AC:50354	Hom:10451	AN:122758	Cov:
Turkish Variome	AF: 0.0712	AC:110	Hom:5	AN:1546	Cov:
UK10K	AF: 0.0722	AC:546	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.386	AC:3457	Hom:692	AN:8960	Cov:

Showing 14 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.80
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.74
GPN-Star LLR	N/A	0.47
GPN-Star score	N/A	-0.47
PhyloP100	Benign	-0.49

Showing 7 of 7 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs733618;

hg19: chr2-204730944;

COSMIC: COSV107314265;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar