chr19-42003351-C-A

Variant names:

• chr19-42003351-C-A
• rs150595206
• NM_002088.5:c.2495G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002088.5(GRIK5):​c.2495G>T​(p.Arg832Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,036 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (162 hom.)
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.85
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061793923).
• BP6: Variant 19-42003351-C-A is Benign according to our data. Variant chr19-42003351-C-A is described in ClinVar as Benign. ClinVar VariationId is 779044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

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.2495G>T	p.Arg832Met	missense	Exon 19 of 20	NP_002079.3
	GRIK5	NM_001301030.2		c.2495G>T	p.Arg832Met	missense	Exon 19 of 20	NP_001287959.1	Q16478-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK5	ENST00000593562.6	TSL:5 MANE Select	c.2495G>T	p.Arg832Met	missense	Exon 19 of 20	ENSP00000470251.1	Q16478-1
	GRIK5	ENST00000301218.8	TSL:1	c.2495G>T	p.Arg832Met	missense	Exon 18 of 19	ENSP00000301218.3	Q16478-2
	GRIK5	ENST00000262895.7	TSL:1	c.2495G>T	p.Arg832Met	missense	Exon 18 of 19	ENSP00000262895.2	Q16478-1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 673 AN: 151926 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0109 AC: 2745 AN: 250790 AF XY: 0.00841

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0777

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00228 AC: 3335 AN: 1460992 Hom.: 162 Cov.: 34 AF XY: 0.00191 AC XY: 1386 AN XY: 726786

African (AFR) AF: 0.00125 AC: 42 AN: 33468

American (AMR) AF: 0.0708 AC: 3166 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111580

Other (OTH) AF: 0.00161 AC: 97 AN: 60370

GnomAD4 genome AF: 0.00443 AC: 673 AN: 152044 Hom.: 25 Cov.: 32 AF XY: 0.00527 AC XY: 392 AN XY: 74324

African (AFR) AF: 0.00159 AC: 66 AN: 41466

American (AMR) AF: 0.0389 AC: 594 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67968

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00121 Hom.: 10

Bravo AF: 0.00758

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00788 AC: 957

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GRIK5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.89	P
Vest4		0.64
MPC		1.6
ClinPred		0.057	T
GERP RS		4.2
Varity_R		0.22
gMVP		0.61
Mutation Taster		=63/37	polymorphism (auto)

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

Other links and lift over

dbSNP: rs150595206; hg19: chr19-42507503; COSMIC: COSV104542671;