4-93108338-T-C

Variant names:

• chr4-93108338-T-C
• rs4693305
• NM_001510.4:c.530-2410T>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.530-2410T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 152,026 control chromosomes in the GnomAD database, including 15,651 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 0.44 (15651 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709
• Publications: 7 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.584 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.530-2410T>C		intron	N/A	NP_001501.2	O43424-1
	GRID2	NM_001440459.1		c.530-2410T>C		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.245-2410T>C		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.530-2410T>C		intron	N/A	ENSP00000282020.4	O43424-1
	GRID2	ENST00000611049.4	TSL:1	c.287-2410T>C		intron	N/A	ENSP00000483084.1	A0A087X043
	GRID2	ENST00000510992.5	TSL:1	c.245-2410T>C		intron	N/A	ENSP00000421257.1	O43424-2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67447 AN: 151908 Hom.: 15624 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.466

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

GnomAD4 genome AF: 0.444 AC: 67527 AN: 152026 Hom.: 15651 Cov.: 32 AF XY: 0.447 AC XY: 33202 AN XY: 74314

African (AFR) AF: 0.514 AC: 21307 AN: 41460

American (AMR) AF: 0.594 AC: 9071 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1838 AN: 3466

East Asian (EAS) AF: 0.519 AC: 2675 AN: 5150

South Asian (SAS) AF: 0.423 AC: 2041 AN: 4822

European-Finnish (FIN) AF: 0.323 AC: 3417 AN: 10568

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25552 AN: 67972

Other (OTH) AF: 0.467 AC: 985 AN: 2110

Alfa AF: 0.384 Hom.: 6934

Bravo AF: 0.471

Asia WGS AF: 0.508 AC: 1764 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		-0.71
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4693305;

hg19: chr4-94029489;