3-51712803-C-G

Variant names:

• chr3-51712803-C-G
• rs1221775826
• NM_000839.5:c.781C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000839.5(GRM2):​c.781C>G​(p.Pro261Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,612,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRM2 NM_000839.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22712132).

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.781C>G	p.Pro261Ala	missense	Exon 3 of 6	NP_000830.2	Q14416
	GRM2	NM_001349117.2		c.-569C>G		5_prime_UTR	Exon 3 of 7	NP_001336046.1
	GRM2	NM_001349116.2		c.-138-216C>G		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.781C>G	p.Pro261Ala	missense	Exon 3 of 6	ENSP00000378492.3	Q14416
	GRM2	ENST00000296479.9	TSL:1	n.781C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000296479.5	H7BXL3
	GRM2	ENST00000464585.1	TSL:1	n.2460C>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000120 AC: 3 AN: 249368 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460670 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726672

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.37
Sift	Benign	0.033	D
Sift4G	Uncertain	0.054	T
Polyphen		0.020	B
Vest4		0.22
MutPred		0.46		Gain of MoRF binding (P = 0.0608)
MVP		0.40
MPC		0.62
ClinPred		0.13	T
GERP RS		4.4
Varity_R		0.51
gMVP		0.30
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1221775826; hg19: chr3-51746819;