6-146029961-C-G

Variant names:

• chr6-146029961-C-G
• rs138794480
• NM_001278064.2:c.444C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278064.2(GRM1):​c.444C>G​(p.Pro148Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,032 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P148P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: GRM1 NM_001278064.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.446
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-146029961-C-G is Benign according to our data. Variant chr6-146029961-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.446 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000768 (117/152272) while in subpopulation SAS AF = 0.00187 (9/4824). AF 95% confidence interval is 0.000973. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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.444C>G	p.Pro148Pro	synonymous	Exon 1 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.444C>G	p.Pro148Pro	synonymous	Exon 1 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.444C>G	p.Pro148Pro	synonymous	Exon 2 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.444C>G	p.Pro148Pro	synonymous	Exon 1 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.444C>G	p.Pro148Pro	synonymous	Exon 1 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.444C>G	p.Pro148Pro	synonymous	Exon 2 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000688 AC: 173 AN: 251480 AF XY: 0.000714

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00110 AC: 1602 AN: 1461760 Hom.: 5 Cov.: 32 AF XY: 0.00105 AC XY: 760 AN XY: 727208

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00128 AC: 1423 AN: 1111892

Other (OTH) AF: 0.00119 AC: 72 AN: 60392

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74448

African (AFR) AF: 0.000289 AC: 12 AN: 41556

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000849 Hom.: 0

Bravo AF: 0.000744

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.2
DANN	Benign	0.56
PhyloP100		-0.45
PromoterAI		-0.062	Neutral
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: rs138794480; hg19: chr6-146351097;