6-146360021-T-C

Variant names:

• chr6-146360021-T-C
• rs362902
• NM_001278064.2:c.1602+2327T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001278064.2(GRM1):​c.1602+2327T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 152,010 control chromosomes in the GnomAD database, including 20 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 0.015 (20 hom., cov: 32)
• Consequence: GRM1 NM_001278064.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 3 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=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0152 (2303/152010) while in subpopulation NFE AF = 0.0216 (1467/68002). AF 95% confidence interval is 0.0207. There are 20 homozygotes in GnomAd4. There are 1187 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.1602+2327T>C		intron_variant	Intron 5 of 7	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.1602+2327T>C		intron_variant	Intron 5 of 7	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2303 AN: 151894 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00296

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0101

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

GnomAD4 genome AF: 0.0152 AC: 2303 AN: 152010 Hom.: 20 Cov.: 32 AF XY: 0.0160 AC XY: 1187 AN XY: 74342

African (AFR) AF: 0.00295 AC: 122 AN: 41368

American (AMR) AF: 0.00701 AC: 107 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00437 AC: 21 AN: 4810

European-Finnish (FIN) AF: 0.0508 AC: 538 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1467 AN: 68002

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.0203 Hom.: 4

Bravo AF: 0.0113

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.56
PhyloP100		0.17
Mutation Taster		=100/0	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: rs362902; hg19: chr6-146681157;