4-92558124-A-G

Variant names:

• chr4-92558124-A-G
• rs1450500
• NM_001510.4:c.89-32007A>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.89-32007A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 151,872 control chromosomes in the GnomAD database, including 37,708 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 0.69 (37708 hom., cov: 30)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.722
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRID2	NM_001510.4	MANE Select	c.89-32007A>G		intron	N/A	NP_001501.2
	GRID2	NM_001440459.1		c.89-32007A>G		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.89-32007A>G		intron	N/A	NP_001273767.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRID2	ENST00000282020.9	TSL:1 MANE Select	c.89-32007A>G		intron	N/A	ENSP00000282020.4
	GRID2	ENST00000510992.5	TSL:1	c.89-32007A>G		intron	N/A	ENSP00000421257.1
	GRID2	ENST00000505687.5	TSL:1	n.261-32007A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104040 AN: 151754 Hom.: 37653 Cov.: 30

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.686 AC: 104146 AN: 151872 Hom.: 37708 Cov.: 30 AF XY: 0.679 AC XY: 50382 AN XY: 74196

African (AFR) AF: 0.924 AC: 38313 AN: 41482

American (AMR) AF: 0.597 AC: 9090 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2587 AN: 3470

East Asian (EAS) AF: 0.423 AC: 2170 AN: 5130

South Asian (SAS) AF: 0.653 AC: 3144 AN: 4814

European-Finnish (FIN) AF: 0.501 AC: 5270 AN: 10524

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.608 AC: 41328 AN: 67922

Other (OTH) AF: 0.669 AC: 1410 AN: 2108

Alfa AF: 0.629 Hom.: 78649

Bravo AF: 0.701

Asia WGS AF: 0.580 AC: 2021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.5
DANN	Benign	0.45
PhyloP100		0.72
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: rs1450500; hg19: chr4-93479275;