rs231779

Variant names:

• chr2-203869764-C-T
• rs231779
• NM_005214.5:c.110-822C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005214.5(CTLA4):​c.110-822C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 151,892 control chromosomes in the GnomAD database, including 13,184 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13184 hom., cov: 31)
• Consequence: CTLA4 NM_005214.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.712
• Publications: 79 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.110-822C>T		intron_variant	Intron 1 of 3	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.110-822C>T		intron_variant	Intron 1 of 2		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.110-822C>T		intron_variant	Intron 1 of 3		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62225 AN: 151774 Hom.: 13165 Cov.: 31

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.410 AC: 62286 AN: 151892 Hom.: 13184 Cov.: 31 AF XY: 0.416 AC XY: 30860 AN XY: 74240

African (AFR) AF: 0.422 AC: 17459 AN: 41396

American (AMR) AF: 0.416 AC: 6354 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1084 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3328 AN: 5160

South Asian (SAS) AF: 0.317 AC: 1524 AN: 4814

European-Finnish (FIN) AF: 0.510 AC: 5380 AN: 10546

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.382 AC: 25913 AN: 67920

Other (OTH) AF: 0.365 AC: 771 AN: 2112

Alfa AF: 0.388 Hom.: 22929

Bravo AF: 0.408

Asia WGS AF: 0.445 AC: 1543 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs231779; hg19: chr2-204734487;