rs140949805

chr1-108929928-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_013296.5(GPSM2):c.2043G>A(p.Ser681=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,254 control chromosomes in the GnomAD database, including 4 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: GPSM2 NM_013296.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.637

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]

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-108929928-G-A is Benign according to our data. Variant chr1-108929928-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45566.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.637 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0017 (259/152202) while in subpopulation AFR AF= 0.00238 (99/41514). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPSM2	NM_013296.5	c.2043G>A	p.Ser681=	synonymous_variant	15/15	ENST00000264126.9
CLCC1	NM_001377458.1	c.*2619C>T		3_prime_UTR_variant	13/13	ENST00000369969.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPSM2	ENST00000264126.9	c.2043G>A	p.Ser681=	synonymous_variant	15/15	1	NM_013296.5	P1
CLCC1	ENST00000369969.7	c.*2619C>T		3_prime_UTR_variant	13/13	5	NM_001377458.1	P1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00154 AC: 384 AN: 248730 Hom.: 0 AF XY: 0.00148 AC XY: 200 AN XY: 134726

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00125 AC: 1824 AN: 1461052 Hom.: 4 Cov.: 30 AF XY: 0.00129 AC XY: 939 AN XY: 726850

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74428

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GPSM2: BP4, BP7 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser681Ser in Exon 15 of GPSM2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.4% (25/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs140949805). -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2018	- -

Chudley-McCullough syndrome Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.1
Dann	Benign	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: rs140949805; hg19: chr1-109472550;