rs12069435

Variant names:

• chr1-108898950-A-G
• rs12069435
• NM_013296.5:c.753A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_013296.5(GPSM2):​c.753A>G​(p.Ala251Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,611,430 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (229 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (179 hom.)
• Consequence: GPSM2 NM_013296.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.782
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-108898950-A-G is Benign according to our data. Variant chr1-108898950-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.782 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 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.753A>G	p.Ala251Ala	synonymous	Exon 7 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.753A>G	p.Ala251Ala	synonymous	Exon 7 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.753A>G	p.Ala251Ala	synonymous	Exon 7 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.753A>G	p.Ala251Ala	synonymous	Exon 7 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.804A>G	p.Ala268Ala	synonymous	Exon 8 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.804A>G	p.Ala268Ala	synonymous	Exon 9 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4435 AN: 152202 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00799 AC: 2004 AN: 250752 AF XY: 0.00602

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00299 AC: 4368 AN: 1459110 Hom.: 179 Cov.: 29 AF XY: 0.00253 AC XY: 1839 AN XY: 726034

African (AFR) AF: 0.0999 AC: 3332 AN: 33366

American (AMR) AF: 0.00673 AC: 301 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86190

European-Finnish (FIN) AF: 0.000955 AC: 51 AN: 53412

Middle Eastern (MID) AF: 0.00506 AC: 29 AN: 5736

European-Non Finnish (NFE) AF: 0.000250 AC: 277 AN: 1109634

Other (OTH) AF: 0.00609 AC: 367 AN: 60296

GnomAD4 genome AF: 0.0291 AC: 4435 AN: 152320 Hom.: 229 Cov.: 32 AF XY: 0.0277 AC XY: 2061 AN XY: 74484

African (AFR) AF: 0.101 AC: 4180 AN: 41562

American (AMR) AF: 0.0102 AC: 156 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68028

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0148 Hom.: 67

Bravo AF: 0.0332

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.6
DANN	Benign	0.70
PhyloP100		-0.78
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12069435; hg19: chr1-109441572;