4-92425592-T-C

Variant names:

• chr4-92425592-T-C
• rs5021051
• NM_001510.4:c.88+120848T>C

Variant summary

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

The NM_001510.4(GRID2):​c.88+120848T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 151,964 control chromosomes in the GnomAD database, including 48,136 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 0.79 (48136 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRID2	NM_001510.4	c.88+120848T>C		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.88+120848T>C		intron_variant	Intron 1 of 15	1	NM_001510.4	ENSP00000282020.4
GRID2	ENST00000510992.5	c.88+120848T>C		intron_variant	Intron 1 of 14	1		ENSP00000421257.1
GRID2	ENST00000505687.5	n.260+120848T>C		intron_variant	Intron 1 of 5	1

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120686 AN: 151846 Hom.: 48080 Cov.: 32

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.781

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

GnomAD4 genome AF: 0.795 AC: 120797 AN: 151964 Hom.: 48136 Cov.: 32 AF XY: 0.799 AC XY: 59339 AN XY: 74290

African (AFR) AF: 0.791 AC: 32821 AN: 41486

American (AMR) AF: 0.843 AC: 12866 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2310 AN: 3464

East Asian (EAS) AF: 0.905 AC: 4673 AN: 5162

South Asian (SAS) AF: 0.788 AC: 3799 AN: 4820

European-Finnish (FIN) AF: 0.836 AC: 8850 AN: 10586

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.778 AC: 52783 AN: 67876

Other (OTH) AF: 0.783 AC: 1648 AN: 2106

Alfa AF: 0.779 Hom.: 75948

Bravo AF: 0.796

Asia WGS AF: 0.831 AC: 2888 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.63
DANN	Benign	0.51
PhyloP100		-1.4
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: rs5021051; hg19: chr4-93346743;