rs768023437

Variant names:

• chr6-146426563-A-G
• rs768023437
• ENST00000492807.6:c.2665A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-146426563-A-G
• chr6-146426563-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278065.2(GRM1):​c.2665A>G​(p.Arg889Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,068 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R889W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRM1 NM_001278065.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.72
• Publications: 0 publications found

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]

GRM1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 44

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spinocerebellar ataxia 13

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278065.2. 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
	GRM1	NM_001278064.2	MANE Select	c.2661-7309A>G		intron	N/A	NP_001264993.1
	GRM1	NM_001278065.2		c.2665A>G	p.Arg889Gly	missense	Exon 9 of 10	NP_001264994.1
	GRM1	NM_001278066.1		c.2665A>G	p.Arg889Gly	missense	Exon 8 of 9	NP_001264995.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000492807.6	TSL:1	c.2665A>G	p.Arg889Gly	missense	Exon 9 of 10	ENSP00000424095.1
	GRM1	ENST00000507907.1	TSL:1	c.2665A>G	p.Arg889Gly	missense	Exon 8 of 9	ENSP00000425599.1
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.2661-7309A>G		intron	N/A	ENSP00000282753.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460068 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726094

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111220

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.11	D
PhyloP100		5.7
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.98	D
Vest4		0.53
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.68
ClinPred		0.59	D
GERP RS		5.7
Mutation Taster		=75/25	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: rs768023437; hg19: chr6-146747699;