4-92590245-C-T

Position:

chr4-92590245-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001510.4(GRID2):c.203C>T(p.Thr68Met) variant causes a missense change. The variant allele was found at a frequency of 0.0424 in 1,612,220 control chromosomes in the GnomAD database, including 1,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.036 ( 117 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1498 hom. )

Consequence

GRID2
NM_001510.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.14

Variant links:

Genes affected

GRID2 (HGNC:4576): (glutamate ionotropic receptor delta type subunit 2) The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans. [provided by RefSeq, Apr 2014]

GRID2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046738386).

BP6

Variant 4-92590245-C-T is Benign according to our data. Variant chr4-92590245-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1321117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRID2	NM_001510.4 link	c.203C>T	p.Thr68Met	missense_variant	2/16	ENST00000282020.9	NP_001501.2	O43424-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRID2	ENST00000282020.9 link	c.203C>T	p.Thr68Met	missense_variant	2/16	1	NM_001510.4	ENSP00000282020.4	O43424-1
GRID2	ENST00000510992.5 link	c.203C>T	p.Thr68Met	missense_variant	2/15	1		ENSP00000421257.1	O43424-2
GRID2	ENST00000505687.5 link	n.375C>T		non_coding_transcript_exon_variant	2/6	1

Frequencies

GnomAD3 genomes

AF:

0.0359

AC:

5458

AN:

152044

Hom.:

116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0333

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.000969

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.0417

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0475

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0355

AC:

8907

AN:

251148

Hom.:

204

AF XY:

0.0365

AC XY:

4952

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0679

Gnomad EAS exome

AF:

0.000762

Gnomad SAS exome

AF:

0.0204

Gnomad FIN exome

AF:

0.0438

Gnomad NFE exome

AF:

0.0467

Gnomad OTH exome

AF:

0.0412

GnomAD4 exome

AF:

0.0431

AC:

62857

AN:

1460058

Hom.:

1498

Cov.:

AF XY:

0.0424

AC XY:

30806

AN XY:

726370

show subpopulations

Gnomad4 AFR exome

AF:

0.0205

Gnomad4 AMR exome

AF:

0.0237

Gnomad4 ASJ exome

AF:

0.0676

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0198

Gnomad4 FIN exome

AF:

0.0426

Gnomad4 NFE exome

AF:

0.0471

Gnomad4 OTH exome

AF:

0.0442

GnomAD4 genome

AF:

0.0359

AC:

5461

AN:

152162

Hom.:

117

Cov.:

AF XY:

0.0348

AC XY:

2589

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0190

Gnomad4 AMR

AF:

0.0332

Gnomad4 ASJ

AF:

0.0689

Gnomad4 EAS

AF:

0.000972

Gnomad4 SAS

AF:

0.0220

Gnomad4 FIN

AF:

0.0417

Gnomad4 NFE

AF:

0.0476

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0463

Hom.:

332

Bravo

AF:

0.0355

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.0506

AC:

435

ExAC

AF:

0.0351

AC:

4263

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0551

EpiControl

AF:

0.0540

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

GRID2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.13

Sift

Benign

0.060

T;T

Sift4G

Uncertain

0.021

D;D

Polyphen

0.96

D;.

Vest4

0.18

MPC

0.52

ClinPred

0.032

GERP RS

6.0

Varity_R

0.065

gMVP

0.40

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