rs41279678

chr1-108897593-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.16

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]

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]

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]

ACMG classification

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	UniProt
GPSM2	NM_013296.5	c.380G>A	p.Arg127Gln	missense_variant	4/15	ENST00000264126.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14334 AN: 151812 Hom.: 729 Cov.: 32

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

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.: 32 AF XY: 0.0921 AC XY: 66954 AN XY: 726744

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.: 32 AF XY: 0.0928 AC XY: 6886 AN XY: 74220

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	28
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	D
MetaRNN	Benign	0.0087	T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.1	L;.;L;L
MutationTaster	Benign	1.0e-37	P;P;P
PrimateAI	Uncertain	0.78	T
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	T
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

Other links and lift over

dbSNP: rs41279678; hg19: chr1-109440215; COSMIC: COSV51442532; COSMIC: COSV51442532;