rs231775

chr2-203867991-A-Gchr2-203867991-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:3 O:6
• Conservation: PhyloP100: -0.309

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 16921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-203867991-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CTLA4	NM_005214.5	c.49A>G	p.Thr17Ala	missense_variant	1/4	ENST00000648405.2
CTLA4	NM_001037631.3	c.49A>G	p.Thr17Ala	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTLA4	ENST00000648405.2	c.49A>G	p.Thr17Ala	missense_variant	1/4		NM_005214.5	P1

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

GnomAD3 exomes AF: 0.415 AC: 104287 AN: 251236 Hom.: 22926 AF XY: 0.406 AC XY: 55192 AN XY: 135776

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 SAS exome AF: 0.319

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

Gnomad4 AFR exome AF: 0.378

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.391

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

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.644

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.358

Alfa AF: 0.372 Hom.: 22683

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:3 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	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 provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 haploinsuffiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Hashimoto thyroiditis, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Systemic lupus erythematosus, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Thyroid-associated orbitopathy, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Celiac disease, susceptibility to, 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

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
MetaRNN	Benign	0.000025	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;L;L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	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
Varity_R		0.027
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs231775; hg19: chr2-204732714; COSMIC: COSV55592023; COSMIC: COSV55592023;