chr2-203867991-A-G

Variant names:

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

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:5 O:1
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	NM_005214.5	MANE Select	c.49A>G	p.Thr17Ala	missense	Exon 1 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.49A>G	p.Thr17Ala	missense	Exon 1 of 3	NP_001032720.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	ENST00000648405.2	MANE Select	c.49A>G	p.Thr17Ala	missense	Exon 1 of 4	ENSP00000497102.1
	CTLA4	ENST00000487393.1	TSL:1	c.49A>G	p.Thr17Ala	missense	Exon 1 of 2	ENSP00000497319.1
	CTLA4	ENST00000696479.1		c.121A>G	p.Thr41Ala	missense	Exon 2 of 5	ENSP00000512655.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (1)
-	-	1	Hashimoto thyroiditis, susceptibility to (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.31
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.0070
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.0070	B
Vest4		0.047
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;