rs79730689

Variant names:

• chr1-108924138-C-T
• rs79730689
• NM_013296.5:c.1739C>T

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.1739C>T​(p.Ser580Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000273 in 1,613,632 control chromosomes in the GnomAD database, including 2 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 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: GPSM2 NM_013296.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.62
• Publications: 3 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=0.006495118).
• BP6: Variant 1-108924138-C-T is Benign according to our data. Variant chr1-108924138-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178376.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00139 (212/152166) while in subpopulation AFR AF = 0.00484 (201/41502). AF 95% confidence interval is 0.00429. There are 1 homozygotes in GnomAd4. There are 99 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.1739C>T	p.Ser580Leu	missense	Exon 14 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.1739C>T	p.Ser580Leu	missense	Exon 14 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.1739C>T	p.Ser580Leu	missense	Exon 14 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.1739C>T	p.Ser580Leu	missense	Exon 14 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.1790C>T	p.Ser597Leu	missense	Exon 15 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.1790C>T	p.Ser597Leu	missense	Exon 16 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251288 AF XY: 0.000353

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461466 Hom.: 1 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727084

African (AFR) AF: 0.00514 AC: 172 AN: 33474

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111634

Other (OTH) AF: 0.000315 AC: 19 AN: 60384

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74374

African (AFR) AF: 0.00484 AC: 201 AN: 41502

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000469 Hom.: 1

Bravo AF: 0.00164

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Chudley-McCullough syndrome (1)
-	-	1	GPSM2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.053
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0065	T
MetaSVM	Uncertain	0.0058	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.23	T
Sift4G	Benign	0.068	T
Polyphen		0.10	B
Vest4		0.49
MVP		0.92
MPC		0.22
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.097
gMVP		0.44
Mutation Taster		=90/10	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: rs79730689; hg19: chr1-109466760;