rs146996893

Variant names:

• chr6-146398789-C-T
• rs146996893
• NM_001278064.2:c.1750C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001278064.2(GRM1):​c.1750C>T​(p.Arg584Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000881 in 1,611,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R584H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.11
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000877 (128/1459486) while in subpopulation SAS AF = 0.000325 (28/86202). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAdExome4. There are 62 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278064.2. 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.1750C>T	p.Arg584Cys	missense	Exon 7 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.1750C>T	p.Arg584Cys	missense	Exon 7 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.1750C>T	p.Arg584Cys	missense	Exon 8 of 10	NP_001264994.1	Q13255-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.1750C>T	p.Arg584Cys	missense	Exon 7 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.1750C>T	p.Arg584Cys	missense	Exon 7 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.1750C>T	p.Arg584Cys	missense	Exon 8 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251364 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000877 AC: 128 AN: 1459486 Hom.: 0 Cov.: 33 AF XY: 0.0000854 AC XY: 62 AN XY: 726228

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0000856 AC: 95 AN: 1109844

Other (OTH) AF: 0.0000497 AC: 3 AN: 60310

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.033	D
Polyphen		0.99	D
Vest4		0.43
MVP		0.72
MPC		1.3
ClinPred		0.60	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.73
Mutation Taster		=86/14	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: rs146996893; hg19: chr6-146719925; COSMIC: COSV51164930;