rs10516921

Variant names:

• chr4-93456583-A-G
• rs10516921
• NM_001510.4:c.1858+609A>G

Variant summary

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

The NM_001510.4(GRID2):​c.1858+609A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 152,246 control chromosomes in the GnomAD database, including 212 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 0.040 (212 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198
• Publications: 3 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), Orphanet, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 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.1858+609A>G		intron	N/A	NP_001501.2	O43424-1
	GRID2	NM_001440459.1		c.1858+609A>G		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.1573+609A>G		intron	N/A	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.1858+609A>G		intron	N/A	ENSP00000282020.4	O43424-1
	GRID2	ENST00000611049.4	TSL:1	c.1615+609A>G		intron	N/A	ENSP00000483084.1	A0A087X043
	GRID2	ENST00000510992.5	TSL:1	c.1573+609A>G		intron	N/A	ENSP00000421257.1	O43424-2

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6029 AN: 152126 Hom.: 212 Cov.: 32

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0552

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0359

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

GnomAD4 genome AF: 0.0397 AC: 6044 AN: 152246 Hom.: 212 Cov.: 32 AF XY: 0.0384 AC XY: 2856 AN XY: 74444

African (AFR) AF: 0.0969 AC: 4025 AN: 41540

American (AMR) AF: 0.0164 AC: 251 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3470

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5166

South Asian (SAS) AF: 0.0553 AC: 267 AN: 4832

European-Finnish (FIN) AF: 0.0217 AC: 230 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1032 AN: 68014

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0262 Hom.: 25

Bravo AF: 0.0401

Asia WGS AF: 0.0390 AC: 135 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.80
PhyloP100		-0.20
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: rs10516921; hg19: chr4-94377734;