rs231775

Variant names:

• chr2-203867991-A-G
• rs231775
• NM_005214.5:c.49A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-203867991-A-G
• chr2-203867991-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005214.5(CTLA4):​c.49A>G​(p.Thr17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,613,082 control chromosomes in the GnomAD database, including 128,827 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (12592 hom., cov: 32)
  • Exomes 𝑓: 0.39 (116235 hom.)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:6
• Conservation: PhyloP100: -0.309
• Publications: 1065 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.511961E-5).
• BP6: Variant 2-203867991-A-G is Benign according to our data. Variant chr2-203867991-A-G is described in ClinVar as Benign. ClinVar VariationId is 16921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60714 AN: 151936 Hom.: 12575 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.415 AC: 104287 AN: 251236 AF XY: 0.406

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.666

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.393 AC: 573983 AN: 1461028 Hom.: 116235 Cov.: 39 AF XY: 0.390 AC XY: 283226 AN XY: 726866

African (AFR) AF: 0.378 AC: 12658 AN: 33466

American (AMR) AF: 0.454 AC: 20277 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7881 AN: 26128

East Asian (EAS) AF: 0.645 AC: 25599 AN: 39686

South Asian (SAS) AF: 0.321 AC: 27644 AN: 86198

European-Finnish (FIN) AF: 0.529 AC: 28251 AN: 53398

Middle Eastern (MID) AF: 0.264 AC: 1525 AN: 5768

European-Non Finnish (NFE) AF: 0.384 AC: 426516 AN: 1111320

Other (OTH) AF: 0.391 AC: 23632 AN: 60372

GnomAD4 genome AF: 0.400 AC: 60776 AN: 152054 Hom.: 12592 Cov.: 32 AF XY: 0.407 AC XY: 30216 AN XY: 74324

African (AFR) AF: 0.374 AC: 15525 AN: 41480

American (AMR) AF: 0.412 AC: 6308 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3468

East Asian (EAS) AF: 0.644 AC: 3321 AN: 5154

South Asian (SAS) AF: 0.321 AC: 1547 AN: 4812

European-Finnish (FIN) AF: 0.530 AC: 5601 AN: 10574

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.386 AC: 26204 AN: 67960

Other (OTH) AF: 0.358 AC: 756 AN: 2110

Alfa AF: 0.382 Hom.: 48510

Bravo AF: 0.394

TwinsUK AF: 0.372 AC: 1381

ALSPAC AF: 0.381 AC: 1467

ESP6500AA AF: 0.370 AC: 1629

ESP6500EA AF: 0.369 AC: 3176

ExAC AF: 0.411 AC: 49919

Asia WGS AF: 0.445 AC: 1543 AN: 3476

EpiCase AF: 0.358

EpiControl AF: 0.349

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19737153, 19037649, 22497911, 20920330, 21387262, 18757416, 23830732, 21503616, 21612409, 22011251, 19884265, 20145677, 11426323, 21453059, 22905924, 20538028, 23246583, 19922464, 11976786, 12417883, 22699762, 21346773, 21629267, 20940051, 9259273, 24517008, 28220572) -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hashimoto thyroiditis, susceptibility to Other:1

Apr 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO Other:1

Apr 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

THYROID-ASSOCIATED ORBITOPATHY, SUSCEPTIBILITY TO Other:1

Apr 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Systemic lupus erythematosus, susceptibility to Other:1

Apr 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Celiac disease, susceptibility to, 3 Other:1

Apr 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.46
DANN	Benign	0.46
DEOGEN2	Benign	0.24	T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.30	.;T;T;T;T
MetaRNN	Benign	0.000025	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;L;L;L;L
PhyloP100		-0.31
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.28	.;N;N;.;N
REVEL	Benign	0.0070
Sift	Benign	0.18	.;T;T;.;T
Sift4G	Benign	0.21	.;T;T;.;T
Polyphen		0.0070	B;B;.;.;B
Vest4		0.047, 0.059, 0.027
MPC		0.66
ClinPred		0.012	T
GERP RS		-2.8
PromoterAI		-0.071	Neutral
Varity_R		0.027
gMVP		0.33
Mutation Taster		=99/1	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: rs231775; hg19: chr2-204732714; COSMIC: COSV55592023; COSMIC: COSV55592023;