rs231780

Variant names:

• chr2-203871974-G-A
• rs231780
• NM_005214.5:c.567+487G>A

Variant summary

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

The NM_005214.5(CTLA4):​c.567+487G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 152,234 control chromosomes in the GnomAD database, including 71,681 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. The gene CTLA4 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.97 (71681 hom., cov: 31)
• Consequence: CTLA4 NM_005214.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 3 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

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.567+487G>A		intron	N/A	NP_005205.2
	CTLA4	NM_001037631.3		c.458-734G>A		intron	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.567+487G>A		intron	N/A	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000487393.1	TSL:1	c.110-734G>A		intron	N/A	ENSP00000497319.1	P16410-3
	CTLA4	ENST00000696479.1		c.639+487G>A		intron	N/A	ENSP00000512655.1	A0A8Q3SIR7

Frequencies

GnomAD3 genomes AF: 0.969 AC: 147442 AN: 152116 Hom.: 71627 Cov.: 31

Gnomad AFR AF: 0.894

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

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: 1.00

Gnomad OTH AF: 0.978

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

GnomAD4 genome AF: 0.969 AC: 147555 AN: 152234 Hom.: 71681 Cov.: 31 AF XY: 0.970 AC XY: 72200 AN XY: 74440

African (AFR) AF: 0.894 AC: 37133 AN: 41522

American (AMR) AF: 0.989 AC: 15128 AN: 15298

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

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 0.999 AC: 4812 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

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

European-Non Finnish (NFE) AF: 1.00 AC: 68007 AN: 68030

Other (OTH) AF: 0.979 AC: 2069 AN: 2114

Alfa AF: 0.980 Hom.: 9088

Bravo AF: 0.964

Asia WGS AF: 0.994 AC: 3458 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.069
DANN	Benign	0.41
PhyloP100		-1.9
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: rs231780; hg19: chr2-204736697;