rs61758992

Variant names:

• chr1-108922462-T-A
• rs61758992
• NM_013296.5:c.1486T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-108922462-T-A
• chr1-108922462-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_013296.5(GPSM2):​c.1486T>A​(p.Leu496Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,612,620 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).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.425
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033157498).
• BP6: Variant 1-108922462-T-A is Benign according to our data. Variant chr1-108922462-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499162.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000702 (107/152318) while in subpopulation AFR AF = 0.00243 (101/41576). AF 95% confidence interval is 0.00204. There are 0 homozygotes in GnomAd4. There are 60 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.1486T>A	p.Leu496Ile	missense	Exon 13 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.1486T>A	p.Leu496Ile	missense	Exon 13 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.1486T>A	p.Leu496Ile	missense	Exon 13 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.1486T>A	p.Leu496Ile	missense	Exon 13 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.1537T>A	p.Leu513Ile	missense	Exon 14 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.1537T>A	p.Leu513Ile	missense	Exon 15 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251354 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1460302 Hom.: 0 Cov.: 29 AF XY: 0.0000358 AC XY: 26 AN XY: 726580

African (AFR) AF: 0.00197 AC: 66 AN: 33434

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110686

Other (OTH) AF: 0.000182 AC: 11 AN: 60334

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74492

African (AFR) AF: 0.00243 AC: 101 AN: 41576

American (AMR) AF: 0.000262 AC: 4 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000910 Hom.: 0

Bravo AF: 0.000858

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	GPSM2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.42
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.51
Sift	Benign	0.10	T
Sift4G	Benign	0.088	T
Polyphen		0.067	B
Vest4		0.47
MVP		0.91
MPC		0.91
ClinPred		0.072	T
GERP RS		-3.6
Varity_R		0.062
gMVP		0.055
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs61758992; hg19: chr1-109465084;