chr6-146434188-T-C

Variant names:

• chr6-146434188-T-C
• rs6923492
• NM_001278064.2:c.2977T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278064.2(GRM1):​c.2977T>C​(p.Ser993Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 1,612,248 control chromosomes in the GnomAD database, including 229,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25204 hom., cov: 33)
  • Exomes 𝑓: 0.53 (204692 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.127
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9640603E-6).
• BP6: Variant 6-146434188-T-C is Benign according to our data. Variant chr6-146434188-T-C is described in ClinVar as Benign. ClinVar VariationId is 129210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	NM_001278064.2	MANE Select	c.2977T>C	p.Ser993Pro	missense	Exon 8 of 8	NP_001264993.1
	GRM1	NM_001278067.1		c.*215T>C		3_prime_UTR	Exon 8 of 8	NP_001264996.1
	GRM1	NM_001278065.2		c.*341T>C		3_prime_UTR	Exon 10 of 10	NP_001264994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.2977T>C	p.Ser993Pro	missense	Exon 8 of 8	ENSP00000282753.1
	GRM1	ENST00000355289.8	TSL:1	c.*215T>C		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4
	GRM1	ENST00000492807.6	TSL:1	c.*341T>C		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86347 AN: 151972 Hom.: 25163 Cov.: 33

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.521 AC: 129672 AN: 249042 AF XY: 0.525

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.510

Gnomad FIN exome AF: 0.448

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.527 AC: 769036 AN: 1460160 Hom.: 204692 Cov.: 43 AF XY: 0.529 AC XY: 384356 AN XY: 726230

African (AFR) AF: 0.707 AC: 23646 AN: 33432

American (AMR) AF: 0.407 AC: 18203 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 14812 AN: 26096

East Asian (EAS) AF: 0.494 AC: 19598 AN: 39680

South Asian (SAS) AF: 0.600 AC: 51747 AN: 86204

European-Finnish (FIN) AF: 0.449 AC: 23962 AN: 53328

Middle Eastern (MID) AF: 0.575 AC: 3314 AN: 5762

European-Non Finnish (NFE) AF: 0.523 AC: 580924 AN: 1110650

Other (OTH) AF: 0.544 AC: 32830 AN: 60312

GnomAD4 genome AF: 0.568 AC: 86437 AN: 152088 Hom.: 25204 Cov.: 33 AF XY: 0.564 AC XY: 41909 AN XY: 74318

African (AFR) AF: 0.704 AC: 29245 AN: 41518

American (AMR) AF: 0.495 AC: 7569 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1965 AN: 3472

East Asian (EAS) AF: 0.517 AC: 2651 AN: 5128

South Asian (SAS) AF: 0.603 AC: 2909 AN: 4824

European-Finnish (FIN) AF: 0.450 AC: 4746 AN: 10558

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35567 AN: 67986

Other (OTH) AF: 0.572 AC: 1208 AN: 2112

Alfa AF: 0.550 Hom.: 26388

Bravo AF: 0.573

TwinsUK AF: 0.523 AC: 1941

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.710 AC: 3129

ESP6500EA AF: 0.533 AC: 4581

ExAC AF: 0.530 AC: 64327

Asia WGS AF: 0.578 AC: 2010 AN: 3478

EpiCase AF: 0.536

EpiControl AF: 0.537

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive spinocerebellar ataxia 13 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Spinocerebellar ataxia 44 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.60
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.13
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.22
Sift	Benign	0.82	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.87
ClinPred		0.00072	T
GERP RS		3.4
Varity_R		0.099
gMVP		0.17
Mutation Taster		=96/4	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: rs6923492; hg19: chr6-146755324; COSMIC: COSV51112948;