2-203867500-T-A

Variant names:

• chr2-203867500-T-A
• rs231774
• ENST00000696479.1:c.48-418T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000696479.1(CTLA4):​c.48-418T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 152,298 control chromosomes in the GnomAD database, including 70,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.96 (70709 hom., cov: 31)
• Consequence: CTLA4 ENST00000696479.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0490
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-203867500-T-A is Benign according to our data. Variant chr2-203867500-T-A is described in ClinVar as Benign. ClinVar VariationId is 1261285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000696479.1	c.48-418T>A		intron_variant	Intron 1 of 4			ENSP00000512655.1

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146397 AN: 152180 Hom.: 70663 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

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

GnomAD4 genome AF: 0.962 AC: 146502 AN: 152298 Hom.: 70709 Cov.: 31 AF XY: 0.963 AC XY: 71681 AN XY: 74462

African (AFR) AF: 0.870 AC: 36133 AN: 41534

American (AMR) AF: 0.984 AC: 15065 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3425 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 0.999 AC: 4804 AN: 4808

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67999 AN: 68040

Other (OTH) AF: 0.974 AC: 2061 AN: 2116

Alfa AF: 0.975 Hom.: 9009

Bravo AF: 0.956

Asia WGS AF: 0.991 AC: 3448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

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	-0.74
CADD	Benign	2.7
DANN	Benign	0.75
PhyloP100		-0.049
PromoterAI		-0.0018	Neutral

Splicing

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

Other links and lift over

dbSNP: rs231774; hg19: chr2-204732223;