rs2942

Positions:

• chr6-146434004-G-A
• chr6-146434004-G-C
• chr6-146434004-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001278064.2(GRM1):​c.2793G>A​(p.Lys931Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,152 control chromosomes in the GnomAD database, including 218,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19385 hom., cov: 32)
  • Exomes 𝑓: 0.52 (198681 hom.)
• Consequence: GRM1 NM_001278064.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.44

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-146434004-G-A is Benign according to our data. Variant chr6-146434004-G-A is described in ClinVar as [Benign]. Clinvar id is 129209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434004-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.2793G>A	p.Lys931Lys	synonymous_variant	8/8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.2793G>A	p.Lys931Lys	synonymous_variant	8/8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76545 AN: 151844 Hom.: 19359 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.512

GnomAD3 exomes AF: 0.504 AC: 126597 AN: 251376 Hom.: 32626 AF XY: 0.512 AC XY: 69552 AN XY: 135872

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.509

Gnomad SAS exome AF: 0.600

Gnomad FIN exome AF: 0.448

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.519 AC: 758842 AN: 1461188 Hom.: 198681 Cov.: 46 AF XY: 0.523 AC XY: 380004 AN XY: 726938

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.599

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.504 AC: 76608 AN: 151964 Hom.: 19385 Cov.: 32 AF XY: 0.502 AC XY: 37242 AN XY: 74242

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.516

Alfa AF: 0.524 Hom.: 48836

Bravo AF: 0.500

Asia WGS AF: 0.566 AC: 1971 AN: 3478

EpiCase AF: 0.534

EpiControl AF: 0.535

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive spinocerebellar ataxia 13 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Spinocerebellar ataxia 44 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.3
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs2942; hg19: chr6-146755140; COSMIC: COSV51124862;