NM_001510.4:c.203C>T

Variant names:

• chr4-92590245-C-T
• rs34144324
• NM_001510.4:c.203C>T

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T68R) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 5.14
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 18

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001510.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRID2	NM_001510.4	MANE Select	c.203C>T	p.Thr68Met	missense	Exon 2 of 16	NP_001501.2	O43424-1
	GRID2	NM_001440459.1		c.203C>T	p.Thr68Met	missense	Exon 2 of 16	NP_001427388.1
	GRID2	NM_001286838.1		c.203C>T	p.Thr68Met	missense	Exon 2 of 15	NP_001273767.1	O43424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRID2	ENST00000282020.9	TSL:1 MANE Select	c.203C>T	p.Thr68Met	missense	Exon 2 of 16	ENSP00000282020.4	O43424-1
	GRID2	ENST00000510992.5	TSL:1	c.203C>T	p.Thr68Met	missense	Exon 2 of 15	ENSP00000421257.1	O43424-2
	GRID2	ENST00000505687.5	TSL:1	n.375C>T		non_coding_transcript_exon	Exon 2 of 6

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

GnomAD2 exomes AF: 0.0355 AC: 8907 AN: 251148 AF XY: 0.0365

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 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

African (AFR) AF: 0.0205 AC: 687 AN: 33452

American (AMR) AF: 0.0237 AC: 1060 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 1766 AN: 26114

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39660

South Asian (SAS) AF: 0.0198 AC: 1707 AN: 86190

European-Finnish (FIN) AF: 0.0426 AC: 2274 AN: 53414

Middle Eastern (MID) AF: 0.0595 AC: 343 AN: 5766

European-Non Finnish (NFE) AF: 0.0471 AC: 52340 AN: 1110434

Other (OTH) AF: 0.0442 AC: 2664 AN: 60330

GnomAD4 genome AF: 0.0359 AC: 5461 AN: 152162 Hom.: 117 Cov.: 32 AF XY: 0.0348 AC XY: 2589 AN XY: 74380

African (AFR) AF: 0.0190 AC: 791 AN: 41544

American (AMR) AF: 0.0332 AC: 507 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5146

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4822

European-Finnish (FIN) AF: 0.0417 AC: 441 AN: 10580

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0476 AC: 3236 AN: 67998

Other (OTH) AF: 0.0393 AC: 83 AN: 2114

Alfa AF: 0.0448 Hom.: 578

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GRID2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.13
Sift	Benign	0.060	T
Sift4G	Uncertain	0.021	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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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