3-51709116-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000839.5(GRM2):​c.133G>C​(p.Gly45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G45S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GRM2 NM_000839.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14055821).

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>C	p.Gly45Arg	missense	Exon 2 of 6	NP_000830.2	Q14416
	GRM2	NM_001349117.2		c.-1217G>C		5_prime_UTR	Exon 2 of 7	NP_001336046.1
	GRM2	NM_001349116.2		c.-139+1949G>C		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>C	p.Gly45Arg	missense	Exon 2 of 6	ENSP00000378492.3	Q14416
	GRM2	ENST00000296479.9	TSL:1	n.133G>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000296479.5	H7BXL3
	GRM2	ENST00000464585.1	TSL:1	n.1812G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249714 AF XY: 0.00

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.031
Sift	Benign	0.47	T
Sift4G	Benign	0.41	T
Polyphen		0.47	P
Vest4		0.13
MutPred		0.32		Gain of solvent accessibility (P = 0.0328)
MVP		0.40
MPC		0.77
ClinPred		0.24	T
GERP RS		4.0
PromoterAI		-0.0070	Neutral
Varity_R		0.23
gMVP		0.80
Mutation Taster		=86/14	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;