Genetic Variant NM_014619.5:c.500C>G (chr11-120819909-C-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014619.5(GRIK4):c.500C>G(p.Ala167Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 1,613,830 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 79 hom. )

Consequence

GRIK4
NM_014619.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.53

Publications

9 publications found

Variant links:

Genes affected

GRIK4 (HGNC:4582): (glutamate ionotropic receptor kainate type subunit 4) This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

GRIK4 links:

ENSG00000306735 (HGNC:):

ENSG00000306735 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011505038).

BP6

Variant 11-120819909-C-G is Benign according to our data. Variant chr11-120819909-C-G is described in ClinVar as [Benign]. Clinvar id is 771750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK4	NM_014619.5 link	c.500C>G	p.Ala167Gly	missense_variant	Exon 6 of 21	ENST00000527524.8	NP_055434.2	Q16099A0A8D9PH79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK4	ENST00000527524.8 link	c.500C>G	p.Ala167Gly	missense_variant	Exon 6 of 21	2	NM_014619.5	ENSP00000435648.2		Q16099

Frequencies

GnomAD3 genomes

AF:

0.00592

AC:

901

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00941

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00663

AC:

1664

AN:

251158

AF XY:

0.00715

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00973

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00948

AC:

13853

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00953

AC XY:

6929

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33466

American (AMR)

AF:

0.00219

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00402

AC:

105

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00830

AC:

716

AN:

86236

European-Finnish (FIN)

AF:

0.00792

AC:

423

AN:

53394

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.0108

AC:

12009

AN:

1111916

Other (OTH)

AF:

0.00729

AC:

440

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

648

1296

1944

2592

3240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00591

AC:

900

AN:

152288

Hom.:

Cov.:

AF XY:

0.00598

AC XY:

445

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41562

American (AMR)

AF:

0.00275

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00664

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00792

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00941

AC:

640

AN:

68036

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00722

Hom.:

Bravo

AF:

0.00501

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00675

AC:

819

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00965

EpiControl

AF:

0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;.;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

7.5

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.5

N;.;N

REVEL

Uncertain

0.57

Sift

Benign

0.065

T;.;T

Sift4G

Uncertain

0.045

D;.;D

Polyphen

0.79

P;P;P

Vest4

0.75

MVP

0.43

MPC

0.83

ClinPred

0.047

GERP RS

4.7

Varity_R

0.28

gMVP

0.75

Mutation Taster

=82/18

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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NM_014619.5:c.500C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over