Genetic Variant GRIK5:p.Cys855Trp (chr19-41999249-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002088.5(GRIK5):c.2565C>G(p.Cys855Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,524,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GRIK5
NM_002088.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.678

Publications

0 publications found

Variant links:

Genes affected

GRIK5 (HGNC:4583): (glutamate ionotropic receptor kainate type subunit 5) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

GRIK5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002088.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK5	NM_002088.5	MANE Select	c.2565C>G	p.Cys855Trp	missense	Exon 20 of 20	NP_002079.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIK5	ENST00000593562.6	TSL:5 MANE Select	c.2565C>G	p.Cys855Trp	missense	Exon 20 of 20	ENSP00000470251.1	Q16478-1
GRIK5	ENST00000262895.7	TSL:1	c.2565C>G	p.Cys855Trp	missense	Exon 19 of 19	ENSP00000262895.2	Q16478-1
GRIK5	ENST00000454993.6	TSL:1	n.1442C>G		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1372662

Hom.:

Cov.:

AF XY:

0.00000886

AC XY:

AN XY:

677306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29376

American (AMR)

AF:

0.00

AC:

AN:

34910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24722

East Asian (EAS)

AF:

0.00

AC:

AN:

33916

South Asian (SAS)

AF:

0.00

AC:

AN:

78700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

1074846

Other (OTH)

AF:

0.0000523

AC:

AN:

57380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.13

Eigen_PC

Benign

0.010

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

0.68

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.44

MutPred

0.31

Gain of MoRF binding (P = 0.0654)

MVP

0.24

MPC

2.1

ClinPred

0.99

GERP RS

1.9

Varity_R

0.72

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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