4-92304340-C-T

Position:

• chr4-92304340-C-T

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.-317C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 375,586 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (236 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (29 hom.)
• Consequence: GRID2 ENST00000282020.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.768

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=-0.52).
• BP6: Variant 4-92304340-C-T is Benign according to our data. Variant chr4-92304340-C-T is described in ClinVar as [Benign]. Clinvar id is 1278181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRID2	NM_001510.4	c.-317C>T		5_prime_UTR_variant	1/16	ENST00000282020.9	NP_001501.2
GRID2	XM_017008122.3	c.-317C>T		5_prime_UTR_variant	1/15		XP_016863611.1
GRID2	XM_024454024.2	c.-317C>T		5_prime_UTR_variant	1/17		XP_024309792.1
GRID2	XM_047450133.1	c.-317C>T		5_prime_UTR_variant	1/16		XP_047306089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.-317C>T		5_prime_UTR_variant	1/16	1	NM_001510.4	ENSP00000282020	P1

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4723 AN: 152122 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0230

GnomAD4 exome AF: 0.00327 AC: 730 AN: 223346 Hom.: 29 Cov.: 0 AF XY: 0.00278 AC XY: 340 AN XY: 122174

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.000489

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000515

Gnomad4 OTH exome AF: 0.00771

GnomAD4 genome AF: 0.0311 AC: 4728 AN: 152240 Hom.: 236 Cov.: 32 AF XY: 0.0290 AC XY: 2156 AN XY: 74438

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0269 Hom.: 21

Bravo AF: 0.0354

Asia WGS AF: 0.00318 AC: 11 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	-0.52
CADD	Benign	16
DANN	Benign	0.88

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: rs79693811; hg19: chr4-93225491;