rs189033496

Variant names:

• chr1-108929794-C-T
• rs189033496
• NM_013296.5:c.1909C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP4 BS1

The NM_013296.5(GPSM2):​c.1909C>T​(p.Arg637Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,796 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R637Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.98
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.29417422).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152238) while in subpopulation EAS AF = 0.00251 (13/5188). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1909C>T	p.Arg637Trp	missense	Exon 15 of 15	NP_037428.3
	CLCC1	NM_001377458.1	MANE Select	c.*2753G>A		3_prime_UTR	Exon 13 of 13	NP_001364387.1	Q96S66-1
	GPSM2	NM_001321038.2		c.1909C>T	p.Arg637Trp	missense	Exon 15 of 15	NP_001307967.1	P81274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1909C>T	p.Arg637Trp	missense	Exon 15 of 15	ENSP00000264126.3	P81274
	CLCC1	ENST00000369969.7	TSL:5 MANE Select	c.*2753G>A		3_prime_UTR	Exon 13 of 13	ENSP00000358986.3	Q96S66-1
	GPSM2	ENST00000674914.1		c.1960C>T	p.Arg654Trp	missense	Exon 16 of 16	ENSP00000501579.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251188 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461558 Hom.: 0 Cov.: 30 AF XY: 0.0000564 AC XY: 41 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39688

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111726

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74424

African (AFR) AF: 0.0000241 AC: 1 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Chudley-McCullough syndrome (2)
-	1	1	not provided (2)
-	-	1	GPSM2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.98
MPC		0.86
ClinPred		0.42	T
GERP RS		5.0
Varity_R		0.76
gMVP		0.29
Mutation Taster		=65/35	polymorphism

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: rs189033496; hg19: chr1-109472416; COSMIC: COSV51441884; COSMIC: COSV51441884;