rs750331613

Positions:

chr4-93515346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001510.4(GRID2):c.2128C>T(p.Arg710Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,558 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 Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GRID2
NM_001510.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.102

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-93515346-C-T is Pathogenic according to our data. Variant chr4-93515346-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 427806.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.37606013). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRID2	NM_001510.4 linkuse as main transcript	c.2128C>T	p.Arg710Trp	missense_variant	13/16	ENST00000282020.9	NP_001501.2	O43424-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRID2	ENST00000282020.9 linkuse as main transcript	c.2128C>T	p.Arg710Trp	missense_variant	13/16	1	NM_001510.4	ENSP00000282020.4	O43424-1
GRID2	ENST00000611049.4 linkuse as main transcript	c.1885C>T	p.Arg629Trp	missense_variant	11/14	1		ENSP00000483084.1	A0A087X043
GRID2	ENST00000510992.5 linkuse as main transcript	c.1843C>T	p.Arg615Trp	missense_variant	12/15	1		ENSP00000421257.1	O43424-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251088

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460512

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 18

Pathogenic:1

Pathogenic, no assertion criteria provided

phenotyping only;research

Research Group Niklas Dahl, Uppsala University

Feb 21, 2017

Using whole exome sequencing we identified a homozygous missense variant [c.2128C>T, p.(Arg710Trp)] in GRID2 segregating with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;T

Eigen

Benign

0.088

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.4

D;D;.

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.68

MVP

0.22

MPC

0.82

ClinPred

0.59

GERP RS

2.4

Varity_R

0.48

gMVP

0.79

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