NM_013296.5:c.121C>G

Variant names:

• chr1-108896928-C-G
• rs762581956
• NM_013296.5:c.121C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013296.5(GPSM2):​c.121C>G​(p.Arg41Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPSM2	NM_013296.5	c.121C>G	p.Arg41Gly	missense_variant	Exon 3 of 15	ENST00000264126.9	NP_037428.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9	c.121C>G	p.Arg41Gly	missense_variant	Exon 3 of 15	1	NM_013296.5	ENSP00000264126.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;T;T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	.;D;D;.;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L;.;.;L;L;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.3	D;.;D;.;D;.;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.054	T;.;T;.;T;.;T;D
Sift4G	Benign	0.070	T;.;T;.;T;.;T;D
Polyphen		0.87	P;.;.;P;P;.;.;.
Vest4		0.64
MutPred		0.47		Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);Loss of methylation at R41 (P = 0.0421);
MVP		0.95
MPC		0.48
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.65
gMVP		0.38

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: rs762581956; hg19: chr1-109439550;