Genetic Variant GRM2:p.Ile136Val (chr3-51709389-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000839.5(GRM2):c.406A>G(p.Ile136Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000042 in 1,427,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

GRM2
NM_000839.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.34

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12598819).

BS2

High AC in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM2	NM_000839.5	MANE Select	c.406A>G	p.Ile136Val	missense	Exon 2 of 6	NP_000830.2	Q14416
GRM2	NM_001349117.2		c.-944A>G		5_prime_UTR	Exon 2 of 7	NP_001336046.1
GRM2	NM_001349116.2		c.-139+2222A>G		intron	N/A	NP_001336045.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM2	ENST00000395052.8	TSL:2 MANE Select	c.406A>G	p.Ile136Val	missense	Exon 2 of 6	ENSP00000378492.3	Q14416
GRM2	ENST00000296479.9	TSL:1	n.406A>G		non_coding_transcript_exon	Exon 2 of 7	ENSP00000296479.5	H7BXL3
GRM2	ENST00000464585.1	TSL:1	n.2085A>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

240974

AF XY:

0.00000765

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000930

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000420

AC:

AN:

1427034

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

702270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32968

American (AMR)

AF:

0.0000683

AC:

AN:

43908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25384

East Asian (EAS)

AF:

0.00

AC:

AN:

38744

South Asian (SAS)

AF:

0.00

AC:

AN:

84492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1085414

Other (OTH)

AF:

0.0000170

AC:

AN:

58816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.090

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

M_CAP

Benign

0.0093

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

PhyloP100

5.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.10

REVEL

Benign

0.15

Sift

Benign

0.98

Sift4G

Benign

0.67

Polyphen

0.0020

Vest4

0.23

MutPred

0.55

Gain of glycosylation at T134 (P = 0.1277)

MVP

0.46

MPC

0.50

ClinPred

0.18

GERP RS

3.0

Varity_R

0.13

gMVP

0.33

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over