rs199575734

Variant names:

• chr1-108896993-C-A
• NM_013296.5:c.186C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-108896993-C-A
• chr1-108896993-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013296.5(GPSM2):​c.186C>A​(p.Ser62Arg) 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 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S62S) has been classified as Likely benign.

• 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: -0.109

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPSM2	NM_013296.5	c.186C>A	p.Ser62Arg	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.186C>A	p.Ser62Arg	missense_variant	Exon 3 of 15	1	NM_013296.5	ENSP00000264126.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727068

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;D;D;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.54	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M;.;.;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D;.;D;.;D;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;T;.;D;.;D
Polyphen		1.0	D;.;.;D;D;.;.
Vest4		0.96
MutPred		0.78		Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);Gain of ubiquitination at K59 (P = 0.0708);
MVP		0.96
MPC		0.94
ClinPred		1.0	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109439615;