ENST00000696479.1:c.48-294C>T

Variant names:

• chr2-203867624-C-T
• rs5742909
• ENST00000696479.1:c.48-294C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000696479.1(CTLA4):​c.48-294C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 152,272 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.068 (459 hom., cov: 33)
• Consequence: CTLA4 ENST00000696479.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.123
• Publications: 411 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, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 2-203867624-C-T is Benign according to our data. Variant chr2-203867624-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.-319C>T		upstream_gene_variant		ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.-319C>T		upstream_gene_variant			NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000696479.1	c.48-294C>T		intron_variant	Intron 1 of 4			ENSP00000512655.1
CTLA4	ENST00000648405.2	c.-319C>T		upstream_gene_variant			NM_005214.5	ENSP00000497102.1
CTLA4	ENST00000696049.1	c.-319C>T		upstream_gene_variant				ENSP00000512353.1

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10389 AN: 152154 Hom.: 458 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0933

Gnomad OTH AF: 0.0717

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0682 AC: 10386 AN: 152272 Hom.: 459 Cov.: 33 AF XY: 0.0679 AC XY: 5051 AN XY: 74430

African (AFR) AF: 0.0160 AC: 664 AN: 41568

American (AMR) AF: 0.0698 AC: 1067 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.108 AC: 559 AN: 5166

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4826

European-Finnish (FIN) AF: 0.0967 AC: 1025 AN: 10596

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0933 AC: 6345 AN: 68036

Other (OTH) AF: 0.0714 AC: 151 AN: 2114

Alfa AF: 0.0762 Hom.: 317

Bravo AF: 0.0653

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21387262, 17341658, 16297665, 11426323, 12058260, 20732370, 18396212, 19913589, 11327371, 24298899, 23756164, 26051683) -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.60
PhyloP100		0.12
PromoterAI		0.017	Neutral

Splicing

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

Other links and lift over

dbSNP: rs5742909; hg19: chr2-204732347;