rs61754640

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_013296.5(GPSM2):c.1066G>A(p.Gly356Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,590,706 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.029 ( 726 hom. )

Consequence

GPSM2
NM_013296.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 9.56

Variant links:

Genes affected

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

GPSM2 links:

CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]

CLCC1 links:

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

AKNAD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009292185).

BP6

Variant 1-108904128-G-A is Benign according to our data. Variant chr1-108904128-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45563.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0223 (3386/152120) while in subpopulation NFE AF= 0.0338 (2297/67972). AF 95% confidence interval is 0.0326. There are 60 homozygotes in gnomad4. There are 1557 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPSM2	NM_013296.5 link	c.1066G>A	p.Gly356Arg	missense_variant	Exon 10 of 15	ENST00000264126.9	NP_037428.3	P81274A0A024R0F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9 link	c.1066G>A	p.Gly356Arg	missense_variant	Exon 10 of 15	1	NM_013296.5	ENSP00000264126.3		P81274

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3388

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00585

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0338

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0226

AC:

5667

AN:

251176

Hom.:

AF XY:

0.0227

AC XY:

3086

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00610

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00618

Gnomad FIN exome

AF:

0.0246

Gnomad NFE exome

AF:

0.0335

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0290

AC:

41737

AN:

1438586

Hom.:

726

Cov.:

AF XY:

0.0286

AC XY:

20544

AN XY:

717288

show subpopulations

Gnomad4 AFR exome

AF:

0.00493

Gnomad4 AMR exome

AF:

0.0200

Gnomad4 ASJ exome

AF:

0.0191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00639

Gnomad4 FIN exome

AF:

0.0249

Gnomad4 NFE exome

AF:

0.0335

Gnomad4 OTH exome

AF:

0.0262

GnomAD4 genome

AF:

0.0223

AC:

3386

AN:

152120

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1557

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00583

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00766

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0338

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0299

Hom.:

119

Bravo

AF:

0.0225

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0337

AC:

130

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0329

AC:

283

ExAC

AF:

0.0218

AC:

2652

Asia WGS

AF:

0.00434

AC:

AN:

3472

EpiCase

AF:

0.0342

EpiControl

AF:

0.0366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly356Arg in Exon 10 of GPSM2: This variant is not expected to have clinical sig nificance because it has been identified in 3.3% (233/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61754640). -

Feb 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Chudley-McCullough syndrome

Uncertain:1Benign:1

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;.;D

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Uncertain

-0.063

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.4

D;.;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.020

D;.;D

Sift4G

Uncertain

0.0070

D;.;D

Polyphen

0.99

D;D;D

Vest4

0.31

MutPred

0.29

Gain of phosphorylation at S359 (P = 0.0921);Gain of phosphorylation at S359 (P = 0.0921);Gain of phosphorylation at S359 (P = 0.0921);

MPC

0.91

ClinPred

0.029

GERP RS

5.5

Varity_R

0.77

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over