4-92764254-T-C

Variant names:

• chr4-92764254-T-C
• rs2046015
• NM_001510.4:c.244+173968T>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.244+173968T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 152,018 control chromosomes in the GnomAD database, including 31,048 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 0.62 (31048 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 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.244+173968T>C		intron	N/A	NP_001501.2
	GRID2	NM_001440459.1		c.244+173968T>C		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.244+173968T>C		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.244+173968T>C		intron	N/A	ENSP00000282020.4
	GRID2	ENST00000510992.5	TSL:1	c.244+173968T>C		intron	N/A	ENSP00000421257.1
	GRID2	ENST00000505687.5	TSL:1	n.416+173968T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94102 AN: 151900 Hom.: 30990 Cov.: 32

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.622

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

GnomAD4 genome AF: 0.620 AC: 94222 AN: 152018 Hom.: 31048 Cov.: 32 AF XY: 0.615 AC XY: 45720 AN XY: 74302

African (AFR) AF: 0.842 AC: 34925 AN: 41484

American (AMR) AF: 0.629 AC: 9592 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2351 AN: 3472

East Asian (EAS) AF: 0.552 AC: 2844 AN: 5148

South Asian (SAS) AF: 0.608 AC: 2928 AN: 4818

European-Finnish (FIN) AF: 0.393 AC: 4150 AN: 10548

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35307 AN: 67974

Other (OTH) AF: 0.617 AC: 1302 AN: 2110

Alfa AF: 0.540 Hom.: 2785

Bravo AF: 0.644

Asia WGS AF: 0.638 AC: 2219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.44
PhyloP100		0.14
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: rs2046015; hg19: chr4-93685405;