rs41279678

Positions:

chr1-108897593-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013296.5(GPSM2):c.380G>A(p.Arg127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0924 in 1,612,658 control chromosomes in the GnomAD database, including 7,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 729 hom., cov: 32)

Exomes 𝑓: 0.092 ( 6762 hom. )

Consequence

GPSM2
NM_013296.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 8.16

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:

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:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008746743).

BP6

Variant 1-108897593-G-A is Benign according to our data. Variant chr1-108897593-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-108897593-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPSM2	NM_013296.5 linkuse as main transcript	c.380G>A	p.Arg127Gln	missense_variant	4/15	ENST00000264126.9	NP_037428.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9 linkuse as main transcript	c.380G>A	p.Arg127Gln	missense_variant	4/15	1	NM_013296.5	ENSP00000264126	P1

Frequencies

GnomAD3 genomes

AF:

0.0944

AC:

14334

AN:

151812

Hom.:

729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.0684

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0643

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0843

GnomAD3 exomes

AF:

0.0832

AC:

20917

AN:

251314

Hom.:

1040

AF XY:

0.0844

AC XY:

11464

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.0991

Gnomad AMR exome

AF:

0.0427

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0700

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.0952

GnomAD4 exome

AF:

0.0921

AC:

134585

AN:

1460728

Hom.:

6762

Cov.:

AF XY:

0.0921

AC XY:

66954

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.104

Gnomad4 AMR exome

AF:

0.0450

Gnomad4 ASJ exome

AF:

0.112

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0702

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.0972

Gnomad4 OTH exome

AF:

0.0913

GnomAD4 genome

AF:

0.0944

AC:

14347

AN:

151930

Hom.:

729

Cov.:

AF XY:

0.0928

AC XY:

6886

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.0682

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0649

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.103

Gnomad4 OTH

AF:

0.0834

Alfa

AF:

0.0955

Hom.:

1170

Bravo

AF:

0.0895

TwinsUK

AF:

0.0860

AC:

319

ALSPAC

AF:

0.0947

AC:

365

ESP6500AA

AF:

0.0978

AC:

431

ESP6500EA

AF:

0.0981

AC:

844

ExAC

AF:

0.0863

AC:

10475

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

EpiCase

AF:

0.105

EpiControl

AF:

0.0965

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg127Gln in Exon 04 of GPSM2: This variant is not expected to have clinical sig nificance because it has been identified in 10.3% (385/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41279678). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Chudley-McCullough syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.;D;D

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;.;D

MetaRNN

Benign

0.0087

T;T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.1

L;.;L;L

MutationTaster

Benign

1.0e-37

P;P;P

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.9

D;D;.;D

REVEL

Uncertain

0.61

Sift

Benign

0.055

T;T;.;T

Sift4G

Benign

0.13

T;T;.;T

Polyphen

0.93

P;.;P;P

Vest4

0.18

MPC

0.95

ClinPred

0.012

GERP RS

5.0

Varity_R

0.84

gMVP

0.58

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

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