Genetic Variant GRID2:c.88+30A>T (chr4-92304774-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.00

Publications

0 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), Orphanet, G2P

GRID2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 VariationId 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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRID2	NM_001510.4	MANE Select	c.88+30A>T	intron	N/A	NP_001501.2	O43424-1
GRID2	NM_001440459.1		c.88+30A>T	intron	N/A	NP_001427388.1
GRID2	NM_001286838.1		c.88+30A>T	intron	N/A	NP_001273767.1	O43424-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRID2	ENST00000282020.9	TSL:1 MANE Select	c.88+30A>T	intron	N/A	ENSP00000282020.4	O43424-1
GRID2	ENST00000510992.5	TSL:1	c.88+30A>T	intron	N/A	ENSP00000421257.1	O43424-2
GRID2	ENST00000505687.5	TSL:1	n.260+30A>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00772

AC:

1174

AN:

152038

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000711

AC XY:

472

AN XY:

664158

show subpopulations

African (AFR)

AF:

0.0290

AC:

895

AN:

30836

American (AMR)

AF:

0.00166

AC:

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25298

East Asian (EAS)

AF:

0.00

AC:

AN:

39060

South Asian (SAS)

AF:

0.0000480

AC:

AN:

83274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000545

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

981332

Other (OTH)

AF:

0.00160

AC:

AN:

55702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00774

AC:

1177

AN:

152156

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

571

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0269

AC:

1118

AN:

41524

American (AMR)

AF:

0.00255

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68000

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00397

Hom.:

Bravo

AF:

0.00865

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.5

(source)

DANN

Benign

0.77

PhyloP100

1.0

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over