chr3-51709116-G-A

Variant names:

• chr3-51709116-G-A
• rs764610362
• NM_000839.5:c.133G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000839.5(GRM2):​c.133G>A​(p.Gly45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,459,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GRM2 NM_000839.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

Genes affected

GRM2 (HGNC:4594): (glutamate metabotropic receptor 2) 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 metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033257097).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000839.5. 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
	GRM2	NM_000839.5	MANE Select	c.133G>A	p.Gly45Ser	missense	Exon 2 of 6	NP_000830.2	Q14416
	GRM2	NM_001349117.2		c.-1217G>A		5_prime_UTR	Exon 2 of 7	NP_001336046.1
	GRM2	NM_001349116.2		c.-139+1949G>A		intron	N/A	NP_001336045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM2	ENST00000395052.8	TSL:2 MANE Select	c.133G>A	p.Gly45Ser	missense	Exon 2 of 6	ENSP00000378492.3	Q14416
	GRM2	ENST00000296479.9	TSL:1	n.133G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000296479.5	H7BXL3
	GRM2	ENST00000464585.1	TSL:1	n.1812G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249714 AF XY: 0.0000813

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1459416 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725744

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.000649 AC: 29 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60290

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.029
Sift	Benign	0.72	T
Sift4G	Benign	0.67	T
Polyphen		0.14	B
Vest4		0.079
MutPred		0.29		Loss of catalytic residue at G45 (P = 0.0329)
MVP		0.33
MPC		0.56
ClinPred		0.027	T
GERP RS		4.0
PromoterAI		-0.013	Neutral
Varity_R		0.16
gMVP		0.62
Mutation Taster		=88/12	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: rs764610362; hg19: chr3-51743132;