chr1-108929705-C-T

Position:

• chr1-108929705-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_013296.5(GPSM2):​c.1820C>T​(p.Ser607Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,612,880 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S607S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (14 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.57

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]

GPSM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP6: Variant 1-108929705-C-T is Benign according to our data. Variant chr1-108929705-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00724 (1103/152258) while in subpopulation AFR AF= 0.0252 (1046/41546). AF 95% confidence interval is 0.0239. There are 11 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPSM2	NM_013296.5	c.1820C>T	p.Ser607Phe	missense_variant	15/15	ENST00000264126.9	NP_037428.3
CLCC1	NM_001377458.1	c.*2842G>A		3_prime_UTR_variant	13/13	ENST00000369969.7	NP_001364387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9	c.1820C>T	p.Ser607Phe	missense_variant	15/15	1	NM_013296.5	ENSP00000264126.3
CLCC1	ENST00000369969	c.*2842G>A		3_prime_UTR_variant	13/13	5	NM_001377458.1	ENSP00000358986.3

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152140 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00174 AC: 435 AN: 249668 Hom.: 5 AF XY: 0.00124 AC XY: 167 AN XY: 135156

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000752 AC: 1098 AN: 1460622 Hom.: 14 Cov.: 29 AF XY: 0.000643 AC XY: 467 AN XY: 726698

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00724 AC: 1103 AN: 152258 Hom.: 11 Cov.: 32 AF XY: 0.00657 AC XY: 489 AN XY: 74452

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00117 Hom.: 3

Bravo AF: 0.00822

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser607Phe in Exon 15 of GPSM2: This variant is not expected to have clinical sig nificance because it has been identified in 2.5% (92/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35322815). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;D;D
Vest4		0.81
MVP		0.99
MPC		0.92
ClinPred		0.028	T
GERP RS		5.8
Varity_R		0.84
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35322815; hg19: chr1-109472327;