rs7663835

Variant names:

• chr4-92588008-G-A
• rs7663835
• NM_001510.4:c.89-2123G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001510.4(GRID2):​c.89-2123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 151,920 control chromosomes in the GnomAD database, including 10,967 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (10967 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRID2	NM_001510.4	c.89-2123G>A		intron_variant	Intron 1 of 15	ENST00000282020.9	NP_001501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.89-2123G>A		intron_variant	Intron 1 of 15	1	NM_001510.4	ENSP00000282020.4
GRID2	ENST00000510992.5	c.89-2123G>A		intron_variant	Intron 1 of 14	1		ENSP00000421257.1
GRID2	ENST00000505687.5	n.261-2123G>A		intron_variant	Intron 1 of 5	1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57664 AN: 151800 Hom.: 10945 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.377

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.380 AC: 57732 AN: 151920 Hom.: 10967 Cov.: 32 AF XY: 0.381 AC XY: 28274 AN XY: 74244

African (AFR) AF: 0.394 AC: 16334 AN: 41408

American (AMR) AF: 0.394 AC: 6011 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1466 AN: 3468

East Asian (EAS) AF: 0.424 AC: 2181 AN: 5148

South Asian (SAS) AF: 0.435 AC: 2098 AN: 4826

European-Finnish (FIN) AF: 0.321 AC: 3383 AN: 10542

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24954 AN: 67948

Other (OTH) AF: 0.374 AC: 788 AN: 2106

Alfa AF: 0.368 Hom.: 1611

Bravo AF: 0.386

Asia WGS AF: 0.465 AC: 1614 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.076
Mutation Taster		=100/0	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: rs7663835; hg19: chr4-93509159;