2-203874002-C-T

Variant names:

• chr2-203874002-C-T
• rs231721
• NM_005214.5:c.*1190C>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.*1190C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 201,390 control chromosomes in the GnomAD database, including 98,978 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 0.99 (74524 hom., cov: 32)
  • Exomes 𝑓: 1.0 (24454 hom.)
• Consequence: CTLA4 NM_005214.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005214.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	NM_005214.5	MANE Select	c.*1190C>T		downstream_gene	N/A	NP_005205.2
	CTLA4	NM_001037631.3		c.*1227C>T		downstream_gene	N/A	NP_001032720.1	P16410-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	ENST00000648405.2	MANE Select	c.*1190C>T		downstream_gene	N/A	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*1190C>T		downstream_gene	N/A	ENSP00000512655.1	A0A8Q3SIR7

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150530 AN: 152204 Hom.: 74467 Cov.: 32

Gnomad AFR AF: 0.961

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 0.998 AC: 48986 AN: 49068 Hom.: 24454 Cov.: 0 AF XY: 0.999 AC XY: 22723 AN XY: 22754

African (AFR) AF: 0.966 AC: 1880 AN: 1946

American (AMR) AF: 0.997 AC: 1354 AN: 1358

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3168 AN: 3168

East Asian (EAS) AF: 1.00 AC: 8006 AN: 8008

South Asian (SAS) AF: 1.00 AC: 440 AN: 440

European-Finnish (FIN) AF: 1.00 AC: 464 AN: 464

Middle Eastern (MID) AF: 1.00 AC: 296 AN: 296

European-Non Finnish (NFE) AF: 1.00 AC: 29320 AN: 29322

Other (OTH) AF: 0.998 AC: 4058 AN: 4066

GnomAD4 genome AF: 0.989 AC: 150646 AN: 152322 Hom.: 74524 Cov.: 32 AF XY: 0.989 AC XY: 73666 AN XY: 74474

African (AFR) AF: 0.961 AC: 39958 AN: 41566

American (AMR) AF: 0.997 AC: 15251 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4818

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

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68035 AN: 68040

Other (OTH) AF: 0.994 AC: 2100 AN: 2112

Alfa AF: 0.992 Hom.: 10647

Bravo AF: 0.987

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.7
DANN	Benign	0.63
PhyloP100		0.0010
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs231721; hg19: chr2-204738725;