rs41279678

Variant names:

• chr1-108897593-G-A
• rs41279678
• NM_013296.5:c.380G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013296.5(GPSM2):​c.380G>A​(p.Arg127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0924 in 1,612,658 control chromosomes in the GnomAD database, including 7,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (729 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6762 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.16
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008746743).
• BP6: Variant 1-108897593-G-A is Benign according to our data. Variant chr1-108897593-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	NM_013296.5	MANE Select	c.380G>A	p.Arg127Gln	missense	Exon 4 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.380G>A	p.Arg127Gln	missense	Exon 4 of 15	NP_001307967.1
	GPSM2	NM_001321039.3		c.380G>A	p.Arg127Gln	missense	Exon 4 of 16	NP_001307968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.380G>A	p.Arg127Gln	missense	Exon 4 of 15	ENSP00000264126.3
	GPSM2	ENST00000674914.1		c.431G>A	p.Arg144Gln	missense	Exon 5 of 16	ENSP00000501579.1
	GPSM2	ENST00000675087.1		c.431G>A	p.Arg144Gln	missense	Exon 6 of 17	ENSP00000502020.1

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14334 AN: 151812 Hom.: 729 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0643

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0843

GnomAD2 exomes AF: 0.0832 AC: 20917 AN: 251314 AF XY: 0.0844

Gnomad AFR exome AF: 0.0991

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.0921 AC: 134585 AN: 1460728 Hom.: 6762 Cov.: 32 AF XY: 0.0921 AC XY: 66954 AN XY: 726744

African (AFR) AF: 0.104 AC: 3466 AN: 33456

American (AMR) AF: 0.0450 AC: 2014 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2932 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39678

South Asian (SAS) AF: 0.0702 AC: 6051 AN: 86244

European-Finnish (FIN) AF: 0.114 AC: 6063 AN: 53380

Middle Eastern (MID) AF: 0.103 AC: 595 AN: 5766

European-Non Finnish (NFE) AF: 0.0972 AC: 107942 AN: 1111012

Other (OTH) AF: 0.0913 AC: 5511 AN: 60346

GnomAD4 genome AF: 0.0944 AC: 14347 AN: 151930 Hom.: 729 Cov.: 32 AF XY: 0.0928 AC XY: 6886 AN XY: 74220

African (AFR) AF: 0.101 AC: 4175 AN: 41430

American (AMR) AF: 0.0682 AC: 1040 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4820

European-Finnish (FIN) AF: 0.111 AC: 1158 AN: 10478

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6979 AN: 67992

Other (OTH) AF: 0.0834 AC: 176 AN: 2110

Alfa AF: 0.0955 Hom.: 2565

Bravo AF: 0.0895

TwinsUK AF: 0.0860 AC: 319

ALSPAC AF: 0.0947 AC: 365

ESP6500AA AF: 0.0978 AC: 431

ESP6500EA AF: 0.0981 AC: 844

ExAC AF: 0.0863 AC: 10475

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.0965

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Chudley-McCullough syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0087	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.1	L
PhyloP100		8.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.61
Sift	Benign	0.055	T
Sift4G	Benign	0.13	T
Polyphen		0.93	P
Vest4		0.18
MPC		0.95
ClinPred		0.012	T
GERP RS		5.0
PromoterAI		-0.028	Neutral
Varity_R		0.84
gMVP		0.58
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41279678; hg19: chr1-109440215; COSMIC: COSV51442532; COSMIC: COSV51442532;