chr4-93661510-G-A

Variant names:

• chr4-93661510-G-A
• rs6855368
• NM_001510.4:c.2360+35075G>A

Variant summary

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

The NM_001510.4(GRID2):​c.2360+35075G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 152,000 control chromosomes in the GnomAD database, including 24,712 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 0.55 (24712 hom., cov: 32)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908
• 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), G2P, Orphanet

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 (AFR) allele frequency at 95% confidence interval = 0.77 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.2360+35075G>A		intron	N/A	NP_001501.2
	GRID2	NM_001440459.1		c.2360+35075G>A		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.2075+35075G>A		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.2360+35075G>A		intron	N/A	ENSP00000282020.4
	GRID2	ENST00000611049.4	TSL:1	c.2117+35075G>A		intron	N/A	ENSP00000483084.1
	GRID2	ENST00000510992.5	TSL:1	c.2075+35075G>A		intron	N/A	ENSP00000421257.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83539 AN: 151882 Hom.: 24671 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.527

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

GnomAD4 genome AF: 0.550 AC: 83637 AN: 152000 Hom.: 24712 Cov.: 32 AF XY: 0.553 AC XY: 41104 AN XY: 74302

African (AFR) AF: 0.777 AC: 32218 AN: 41476

American (AMR) AF: 0.476 AC: 7274 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1585 AN: 3472

East Asian (EAS) AF: 0.669 AC: 3455 AN: 5162

South Asian (SAS) AF: 0.514 AC: 2478 AN: 4822

European-Finnish (FIN) AF: 0.481 AC: 5066 AN: 10536

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29889 AN: 67946

Other (OTH) AF: 0.529 AC: 1112 AN: 2104

Alfa AF: 0.482 Hom.: 57002

Bravo AF: 0.561

Asia WGS AF: 0.603 AC: 2094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.50
PhyloP100		0.91
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: rs6855368; hg19: chr4-94582661;