Genetic Variant GRID2:c.88+118617T>C (chr4-92423361-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001510.4(GRID2):c.88+118617T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 151,960 control chromosomes in the GnomAD database, including 45,575 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 0.77 ( 45575 hom., cov: 31)

Consequence

GRID2
NM_001510.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.249

Publications

2 publications found

Variant links:

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

GRID2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRID2	NM_001510.4 link	c.88+118617T>C		intron_variant	Intron 1 of 15	ENST00000282020.9	NP_001501.2	O43424-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRID2	ENST00000282020.9 link	c.88+118617T>C	intron_variant	Intron 1 of 15	1	NM_001510.4	ENSP00000282020.4	O43424-1
GRID2	ENST00000510992.5 link	c.88+118617T>C	intron_variant	Intron 1 of 14	1		ENSP00000421257.1	O43424-2
GRID2	ENST00000505687.5 link	n.260+118617T>C	intron_variant	Intron 1 of 5	1

Frequencies

GnomAD3 genomes

AF:

0.773

AC:

117375

AN:

151842

Hom.:

45519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.784

Gnomad AMI

AF:

0.908

Gnomad AMR

AF:

0.817

Gnomad ASJ

AF:

0.659

Gnomad EAS

AF:

0.905

Gnomad SAS

AF:

0.784

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.743

Gnomad OTH

AF:

0.765

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

GnomAD4 genome

AF:

0.773

AC:

117486

AN:

151960

Hom.:

45575

Cov.:

AF XY:

0.779

AC XY:

57841

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.784

AC:

32518

AN:

41468

American (AMR)

AF:

0.817

AC:

12452

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.659

AC:

2288

AN:

3472

East Asian (EAS)

AF:

0.905

AC:

4658

AN:

5146

South Asian (SAS)

AF:

0.783

AC:

3773

AN:

4816

European-Finnish (FIN)

AF:

0.822

AC:

8669

AN:

10546

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.743

AC:

50494

AN:

67964

Other (OTH)

AF:

0.767

AC:

1615

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1344

2689

4033

5378

6722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.755

Hom.:

110850

Bravo

AF:

0.774

Asia WGS

AF:

0.827

AC:

2873

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.9

(source)

DANN

Benign

0.59

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over