rs766470483

Variant names:

• chr4-92590159-G-T
• rs766470483
• NM_001510.4:c.117G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001510.4(GRID2):​c.117G>T​(p.Lys39Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,459,970 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GRID2 NM_001510.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41163415).

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.117G>T	p.Lys39Asn	missense	Exon 2 of 16	NP_001501.2	O43424-1
	GRID2	NM_001440459.1		c.117G>T	p.Lys39Asn	missense	Exon 2 of 16	NP_001427388.1
	GRID2	NM_001286838.1		c.117G>T	p.Lys39Asn	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.117G>T	p.Lys39Asn	missense	Exon 2 of 16	ENSP00000282020.4	O43424-1
	GRID2	ENST00000510992.5	TSL:1	c.117G>T	p.Lys39Asn	missense	Exon 2 of 15	ENSP00000421257.1	O43424-2
	GRID2	ENST00000505687.5	TSL:1	n.289G>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250754 AF XY: 0.00000738

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1459970 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726414

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110482

Other (OTH) AF: 0.0000166 AC: 1 AN: 60328

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.057
Eigen_PC	Benign	0.0012
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.70
MutPred		0.45		Loss of ubiquitination at K39 (P = 0.0297)
MVP		0.82
MPC		0.57
ClinPred		0.11	T
GERP RS		3.2
Varity_R		0.074
gMVP		0.56
Mutation Taster		=37/63	disease causing

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: rs766470483; hg19: chr4-93511310;