chr4-92304774-A-T

Variant names:

• chr4-92304774-A-T
• rs114432116
• NM_001510.4:c.88+30A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001510.4(GRID2):​c.88+30A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,471,020 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (15 hom.)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-92304774-A-T is Benign according to our data. Variant chr4-92304774-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1722914.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00774 (1177/152156) while in subpopulation AFR AF = 0.0269 (1118/41524). AF 95% confidence interval is 0.0256. There are 17 homozygotes in GnomAd4. There are 571 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRID2	NM_001510.4	c.88+30A>T		intron_variant	Intron 1 of 15	ENST00000282020.9	NP_001501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.88+30A>T		intron_variant	Intron 1 of 15	1	NM_001510.4	ENSP00000282020.4
GRID2	ENST00000510992.5	c.88+30A>T		intron_variant	Intron 1 of 14	1		ENSP00000421257.1
GRID2	ENST00000505687.5	n.260+30A>T		intron_variant	Intron 1 of 5	1

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1174 AN: 152038 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00210 AC: 522 AN: 248750 AF XY: 0.00151

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000836 AC: 1103 AN: 1318864 Hom.: 15 Cov.: 21 AF XY: 0.000711 AC XY: 472 AN XY: 664158

Gnomad4 AFR exome AF: 0.0290 AC: 895 AN: 30836

Gnomad4 AMR exome AF: 0.00166 AC: 74 AN: 44506

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25298

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39060

Gnomad4 SAS exome AF: 0.0000480 AC: 4 AN: 83274

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53352

Gnomad4 NFE exome AF: 0.0000387 AC: 38 AN: 981332

Gnomad4 Remaining exome AF: 0.00160 AC: 89 AN: 55702

GnomAD4 genome AF: 0.00774 AC: 1177 AN: 152156 Hom.: 17 Cov.: 32 AF XY: 0.00768 AC XY: 571 AN XY: 74392

Gnomad4 AFR AF: 0.0269 AC: 0.0269242 AN: 0.0269242

Gnomad4 AMR AF: 0.00255 AC: 0.00255202 AN: 0.00255202

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000735294 AN: 0.0000735294

Gnomad4 OTH AF: 0.00617 AC: 0.00616698 AN: 0.00616698

Alfa AF: 0.00397 Hom.: 4

Bravo AF: 0.00865

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 07, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.5
DANN	Benign	0.77
Mutation Taster		=100/0	polymorphism

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: rs114432116; hg19: chr4-93225925;