Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_021956.5(GRIK2):c.939T>C(p.Asp313Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,612,992 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 35 hom. )

Consequence

GRIK2
NM_021956.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.96

Publications

1 publications found

Variant links:

Genes affected

GRIK2 (HGNC:4580): (glutamate ionotropic receptor kainate type subunit 2) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. Mutations in this gene have been associated with autosomal recessive cognitive disability. [provided by RefSeq, Jul 2008]

GRIK2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
intellectual disability, autosomal recessive 6
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
neurodevelopmental disorder with impaired language and ataxia and with or without seizures
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GRIK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 6-101686341-T-C is Benign according to our data. Variant chr6-101686341-T-C is described in ClinVar as Benign. ClinVar VariationId is 129177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.96 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00965 (1469/152232) while in subpopulation AFR AF = 0.0247 (1028/41550). AF 95% confidence interval is 0.0235. There are 13 homozygotes in GnomAd4. There are 692 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIK2	NM_021956.5	MANE Select	c.939T>C	p.Asp313Asp	synonymous	Exon 7 of 17	NP_068775.1
GRIK2	NM_001166247.1		c.939T>C	p.Asp313Asp	synonymous	Exon 6 of 17	NP_001159719.1
GRIK2	NM_175768.3		c.939T>C	p.Asp313Asp	synonymous	Exon 6 of 17	NP_786944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.939T>C	p.Asp313Asp	synonymous	Exon 7 of 17	ENSP00000358130.6
GRIK2	ENST00000421544.6	TSL:1	c.939T>C	p.Asp313Asp	synonymous	Exon 9 of 19	ENSP00000397026.1
GRIK2	ENST00000369138.5	TSL:1	c.939T>C	p.Asp313Asp	synonymous	Exon 6 of 17	ENSP00000358134.1

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1468

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00479

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00476

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00446

AC:

1119

AN:

251010

AF XY:

0.00410

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00465

AC:

6789

AN:

1460760

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

3278

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.0251

AC:

839

AN:

33442

American (AMR)

AF:

0.00297

AC:

133

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.000290

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.000656

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00479

AC:

5323

AN:

1111104

Other (OTH)

AF:

0.00517

AC:

312

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

331

661

992

1322

1653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.00965

AC:

1469

AN:

152232

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

692

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0247

AC:

1028

AN:

41550

American (AMR)

AF:

0.00478

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00476

AC:

324

AN:

68006

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

143

214

286

357

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:

0.00747

Hom.:

Bravo

AF:

0.0108

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00511

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

2.0

Mutation Taster

=69/31

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_021956.5:c.939T>C

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over