Genetic Variant GRM2:p.Ala248Val (chr3-51712765-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000839.5(GRM2):c.743C>T(p.Ala248Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,613,348 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

GRM2
NM_000839.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.34

Variant links:

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]

GRM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042814016).

BP6

Variant 3-51712765-C-T is Benign according to our data. Variant chr3-51712765-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 737829.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM2	NM_000839.5 link	c.743C>T	p.Ala248Val	missense_variant	Exon 3 of 6	ENST00000395052.8	NP_000830.2	Q14416

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM2	ENST00000395052.8 link	c.743C>T	p.Ala248Val	missense_variant	Exon 3 of 6	2	NM_000839.5	ENSP00000378492.3		Q14416

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00220

AC:

550

AN:

249848

Hom.:

AF XY:

0.00207

AC XY:

281

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00580

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00385

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00252

AC:

3685

AN:

1460994

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1743

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00693

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00441

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00214

AC:

326

AN:

152354

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00323

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00231

AC:

281

EpiCase

AF:

0.00289

EpiControl

AF:

0.00255

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.31

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.81

L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.17

Sift

Benign

0.10

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.051

B;.

Vest4

0.078

MVP

0.40

MPC

0.59

ClinPred

0.012

GERP RS

4.4

Varity_R

0.10

gMVP

0.44

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over