chr4-92590330-G-A

Position:

• chr4-92590330-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000282020.9(GRID2):​c.244+44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,411,106 control chromosomes in the GnomAD database, including 98,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (10973 hom., cov: 32)
  • Exomes 𝑓: 0.37 (87388 hom.)
• Consequence: GRID2 ENST00000282020.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0950

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-92590330-G-A is Benign according to our data. Variant chr4-92590330-G-A is described in ClinVar as [Benign]. Clinvar id is 1293383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRID2	NM_001510.4	c.244+44G>A		intron_variant		ENST00000282020.9	NP_001501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.244+44G>A		intron_variant		1	NM_001510.4	ENSP00000282020	P1
GRID2	ENST00000510992.5	c.244+44G>A		intron_variant		1		ENSP00000421257
GRID2	ENST00000505687.5	n.416+44G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57666 AN: 151770 Hom.: 10951 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.378

GnomAD3 exomes AF: 0.380 AC: 84905 AN: 223720 Hom.: 16421 AF XY: 0.383 AC XY: 46392 AN XY: 121194

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.448

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.371 AC: 467606 AN: 1259218 Hom.: 87388 Cov.: 16 AF XY: 0.374 AC XY: 235885 AN XY: 630718

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.380 AC: 57734 AN: 151888 Hom.: 10973 Cov.: 32 AF XY: 0.381 AC XY: 28270 AN XY: 74246

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.423

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.376

Alfa AF: 0.369 Hom.: 2010

Bravo AF: 0.386

Asia WGS AF: 0.467 AC: 1626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs2870639; hg19: chr4-93511481;