rs61754640

Variant names:

• chr1-108904128-G-A
• rs61754640
• NM_013296.5:c.1066G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-108904128-G-A
• chr1-108904128-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013296.5(GPSM2):​c.1066G>A​(p.Gly356Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,590,706 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (726 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 9.56
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009292185).
• BP6: Variant 1-108904128-G-A is Benign according to our data. Variant chr1-108904128-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45563.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3386/152120) while in subpopulation NFE AF = 0.0338 (2297/67972). AF 95% confidence interval is 0.0326. There are 60 homozygotes in GnomAd4. There are 1557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

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.1066G>A	p.Gly356Arg	missense	Exon 10 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.1066G>A	p.Gly356Arg	missense	Exon 10 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.1066G>A	p.Gly356Arg	missense	Exon 10 of 16	NP_001307968.1	P81274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1066G>A	p.Gly356Arg	missense	Exon 10 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.1117G>A	p.Gly373Arg	missense	Exon 11 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.1117G>A	p.Gly373Arg	missense	Exon 12 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3388 AN: 152004 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00585

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0226 AC: 5667 AN: 251176 AF XY: 0.0227

Gnomad AFR exome AF: 0.00610

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0290 AC: 41737 AN: 1438586 Hom.: 726 Cov.: 26 AF XY: 0.0286 AC XY: 20544 AN XY: 717288

African (AFR) AF: 0.00493 AC: 163 AN: 33086

American (AMR) AF: 0.0200 AC: 892 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 495 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00639 AC: 548 AN: 85772

European-Finnish (FIN) AF: 0.0249 AC: 1329 AN: 53344

Middle Eastern (MID) AF: 0.0364 AC: 184 AN: 5056

European-Non Finnish (NFE) AF: 0.0335 AC: 36565 AN: 1091766

Other (OTH) AF: 0.0262 AC: 1561 AN: 59550

GnomAD4 genome AF: 0.0223 AC: 3386 AN: 152120 Hom.: 60 Cov.: 32 AF XY: 0.0209 AC XY: 1557 AN XY: 74378

African (AFR) AF: 0.00583 AC: 242 AN: 41514

American (AMR) AF: 0.0220 AC: 336 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.0261 AC: 275 AN: 10546

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2297 AN: 67972

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0295 Hom.: 251

Bravo AF: 0.0225

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0329 AC: 283

ExAC AF: 0.0218 AC: 2652

Asia WGS AF: 0.00434 AC: 15 AN: 3472

EpiCase AF: 0.0342

EpiControl AF: 0.0366

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Chudley-McCullough syndrome (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.31
MutPred		0.29		Gain of phosphorylation at S359 (P = 0.0921)
MPC		0.91
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.77
gMVP		0.50
Mutation Taster		=41/59	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61754640; hg19: chr1-109446750; COSMIC: COSV51443826;