chr1-108885572-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013296.5(GPSM2):​c.50G>A​(p.Arg17His) variant causes a missense change. The variant allele was found at a frequency of 0.000021 in 1,573,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GPSM2
NM_013296.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.29
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25875667).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPSM2NM_013296.5 linkuse as main transcriptc.50G>A p.Arg17His missense_variant 2/15 ENST00000264126.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPSM2ENST00000264126.9 linkuse as main transcriptc.50G>A p.Arg17His missense_variant 2/151 NM_013296.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249742
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135204
show subpopulations
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000218
AC:
31
AN:
1421526
Hom.:
0
Cov.:
24
AF XY:
0.0000211
AC XY:
15
AN XY:
709738
show subpopulations
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:
0.0000270
Gnomad4 OTH exome
AF:
0.0000339
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 18, 2021This sequence change replaces arginine with histidine at codon 17 of the GPSM2 protein (p.Arg17His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs773654932, ExAC 0.003%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GPSM2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.032
T;.;.;T;T;.;.;.
Eigen
Benign
-0.10
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
.;D;D;.;D;D;D;D
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.26
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Benign
0.46
N;.;.;N;N;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.23
N;.;N;.;N;.;N;N
REVEL
Benign
0.24
Sift
Benign
0.043
D;.;T;.;D;.;T;T
Sift4G
Benign
0.29
T;.;T;.;T;.;T;T
Polyphen
0.027
B;.;.;B;B;.;.;.
Vest4
0.31
MutPred
0.42
Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);Loss of methylation at R17 (P = 0.0262);
MVP
0.97
MPC
0.30
ClinPred
0.43
T
GERP RS
4.7
Varity_R
0.37
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773654932; hg19: chr1-109428194; API