rs34144324

chr4-92590245-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. T68T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (117 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1498 hom.)
• Consequence: GRID2 NM_001510.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.14

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]

ACMG classification

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	UniProt
GRID2	NM_001510.4	c.203C>T	p.Thr68Met	missense_variant	2/16	ENST00000282020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRID2	ENST00000282020.9	c.203C>T	p.Thr68Met	missense_variant	2/16	1	NM_001510.4	P1
GRID2	ENST00000510992.5	c.203C>T	p.Thr68Met	missense_variant	2/15	1
GRID2	ENST00000505687.5	n.375C>T		non_coding_transcript_exon_variant	2/6	1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5458 AN: 152044 Hom.: 116 Cov.: 32

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

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.: 30 AF XY: 0.0424 AC XY: 30806 AN XY: 726370

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.: 32 AF XY: 0.0348 AC XY: 2589 AN XY: 74380

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: 92

ESP6500EA AF: 0.0506 AC: 435

ExAC AF: 0.0351 AC: 4263

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0551

EpiControl AF: 0.0540

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	See Variant Classification Assertion Criteria. -

GRID2-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.53	D;N
PrimateAI	Uncertain	0.67	T
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	T
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

Other links and lift over

dbSNP: rs34144324; hg19: chr4-93511396; COSMIC: COSV56199249;