rs61754640

chr1-108904128-G-Achr1-108904128-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 9.56

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 -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: {Uncertain_significance=1, Benign=6}.
• 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 GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPSM2	NM_013296.5	c.1066G>A	p.Gly356Arg	missense_variant	10/15	ENST00000264126.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPSM2	ENST00000264126.9	c.1066G>A	p.Gly356Arg	missense_variant	10/15	1	NM_013296.5	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3388 AN: 152004 Hom.: 60 Cov.: 32

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.: 85 AF XY: 0.0227 AC XY: 3086 AN XY: 135766

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.: 26 AF XY: 0.0286 AC XY: 20544 AN XY: 717288

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.: 60 Cov.: 32 AF XY: 0.0209 AC XY: 1557 AN XY: 74378

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: 26

ESP6500EA AF: 0.0329 AC: 283

ExAC AF: 0.0218 AC: 2652

Asia WGS AF: 0.00434 AC: 15 AN: 3472

EpiCase AF: 0.0342

EpiControl AF: 0.0366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Uncertain significance, 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, 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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	32
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	D
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
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	T
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

Other links and lift over

dbSNP: rs61754640; hg19: chr1-109446750; COSMIC: COSV51443826;