6-146424952-C-T

Variant names:

• chr6-146424952-C-T
• rs2268666
• NM_001278064.2:c.2661-8920C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001278064.2(GRM1):​c.2661-8920C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 151,998 control chromosomes in the GnomAD database, including 19,928 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (19928 hom., cov: 33)
• Consequence: GRM1 NM_001278064.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.726
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.2661-8920C>T		intron_variant	Intron 7 of 7	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.2661-8920C>T		intron_variant	Intron 7 of 7	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77579 AN: 151880 Hom.: 19901 Cov.: 33

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.518

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.511 AC: 77646 AN: 151998 Hom.: 19928 Cov.: 33 AF XY: 0.509 AC XY: 37799 AN XY: 74296

African (AFR) AF: 0.496 AC: 20543 AN: 41430

American (AMR) AF: 0.474 AC: 7241 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1956 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3040 AN: 5168

South Asian (SAS) AF: 0.615 AC: 2962 AN: 4816

European-Finnish (FIN) AF: 0.452 AC: 4771 AN: 10544

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35467 AN: 67976

Other (OTH) AF: 0.521 AC: 1100 AN: 2110

Alfa AF: 0.519 Hom.: 11400

Bravo AF: 0.507

Asia WGS AF: 0.598 AC: 2081 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.60
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs2268666; hg19: chr6-146746088; COSMIC: COSV51284317;