Genetic Variant GRID2:p.Ile29Ile (chr4-92304743-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS1

The NM_001510.4(GRID2):c.87C>T(p.Ile29Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,604,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

GRID2
NM_001510.4 splice_region, synonymous

Scores

Splicing: ADA: 0.004902

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.32

Publications

1 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

GRID2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 4-92304743-C-T is Benign according to our data. Variant chr4-92304743-C-T is described in ClinVar as Benign. ClinVar VariationId is 2064428.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00183 (278/152232) while in subpopulation AFR AF = 0.00635 (264/41550). AF 95% confidence interval is 0.00572. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
GRID2	NM_001510.4	MANE Select	c.87C>T	p.Ile29Ile	splice_region synonymous	Exon 1 of 16	NP_001501.2	O43424-1
GRID2	NM_001440459.1		c.87C>T	p.Ile29Ile	splice_region synonymous	Exon 1 of 16	NP_001427388.1
GRID2	NM_001286838.1		c.87C>T	p.Ile29Ile	splice_region synonymous	Exon 1 of 15	NP_001273767.1	O43424-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRID2	ENST00000282020.9	TSL:1 MANE Select	c.87C>T	p.Ile29Ile	splice_region synonymous	Exon 1 of 16	ENSP00000282020.4	O43424-1
GRID2	ENST00000510992.5	TSL:1	c.87C>T	p.Ile29Ile	splice_region synonymous	Exon 1 of 15	ENSP00000421257.1	O43424-2
GRID2	ENST00000505687.5	TSL:1	n.259C>T		splice_region non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

277

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00635

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000522

AC:

130

AN:

249074

AF XY:

0.000430

show subpopulations

Gnomad AFR exome

AF:

0.00683

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000194

AC:

282

AN:

1452312

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

127

AN XY:

723174

show subpopulations

African (AFR)

AF:

0.00673

AC:

224

AN:

33278

American (AMR)

AF:

0.000470

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000816

AC:

AN:

1103336

Other (OTH)

AF:

0.000450

AC:

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00183

AC:

278

AN:

152232

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00635

AC:

264

AN:

41550

American (AMR)

AF:

0.000523

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68012

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0177

Hom.:

2204

Bravo

AF:

0.00192

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

GRID2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.3

PromoterAI

-0.19

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0049

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.010

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