11-124749752-C-T

Variant names:

• chr11-124749752-C-T
• rs148389397
• NM_014312.5:c.542G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_014312.5(VSIG2):​c.542G>A​(p.Arg181His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,613,656 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: VSIG2 NM_014312.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.56
• Publications: 4 publications found

Genes affected

VSIG2 (HGNC:17149): (V-set and immunoglobulin domain containing 2) Predicted to be located in membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051653445).
• BP6: Variant 11-124749752-C-T is Benign according to our data. Variant chr11-124749752-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2588754.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSIG2	NM_014312.5	c.542G>A	p.Arg181His	missense_variant	Exon 4 of 7	ENST00000326621.10	NP_055127.2
VSIG2	NM_001329920.2	c.542G>A	p.Arg181His	missense_variant	Exon 4 of 6		NP_001316849.1
VSIG2	XM_047426684.1	c.542G>A	p.Arg181His	missense_variant	Exon 4 of 5		XP_047282640.1
VSIG2	XM_047426685.1	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 5		XP_047282641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSIG2	ENST00000326621.10	c.542G>A	p.Arg181His	missense_variant	Exon 4 of 7	1	NM_014312.5	ENSP00000318684.5
VSIG2	ENST00000403470.1	c.542G>A	p.Arg181His	missense_variant	Exon 4 of 6	2		ENSP00000385013.1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151752 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251338 AF XY: 0.000228

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000246 AC: 360 AN: 1461790 Hom.: 1 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727194

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000268 AC: 12 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000275 AC: 306 AN: 1111966

Other (OTH) AF: 0.000265 AC: 16 AN: 60390

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151866 Hom.: 0 Cov.: 30 AF XY: 0.000148 AC XY: 11 AN XY: 74254

African (AFR) AF: 0.0000725 AC: 3 AN: 41368

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000600

EpiControl AF: 0.000534

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 25, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.3
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-2.6
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.031
Sift	Benign	0.17	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0090	B;.
Vest4		0.28
MVP		0.040
MPC		0.047
ClinPred		0.017	T
GERP RS		-2.0
Varity_R		0.047
gMVP		0.44
Mutation Taster		=95/5	polymorphism

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: rs148389397; hg19: chr11-124619648; COSMIC: COSV99423216; COSMIC: COSV99423216;