19-41999170-C-T

Variant names:

• chr19-41999170-C-T
• rs1555870287
• NM_002088.5:c.2644G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002088.5(GRIK5):​c.2644G>A​(p.Glu882Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.34

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17739081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK5	NM_002088.5	c.2644G>A	p.Glu882Lys	missense_variant	Exon 20 of 20	ENST00000593562.6	NP_002079.3
GRIK5	XM_011526862.3	c.2647G>A	p.Glu883Lys	missense_variant	Exon 20 of 20		XP_011525164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK5	ENST00000593562.6	c.2644G>A	p.Glu882Lys	missense_variant	Exon 20 of 20	5	NM_002088.5	ENSP00000470251.1
GRIK5	ENST00000262895.7	c.2644G>A	p.Glu882Lys	missense_variant	Exon 19 of 19	1		ENSP00000262895.2
GRIK5	ENST00000454993.6	n.1521G>A		non_coding_transcript_exon_variant	Exon 9 of 9	1
GRIK5	ENST00000602210.1	n.*73G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1355118 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 668768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2644G>A (p.E882K) alteration is located in exon 19 (coding exon 19) of the GRIK5 gene. This alteration results from a G to A substitution at nucleotide position 2644, causing the glutamic acid (E) at amino acid position 882 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.86	N;.
REVEL	Benign	0.037
Sift	Benign	0.079	T;.
Sift4G	Benign	0.81	T;T
Polyphen		0.11	B;B
Vest4		0.27
MutPred		0.29		Gain of ubiquitination at E882 (P = 0.03);Gain of ubiquitination at E882 (P = 0.03);
MVP		0.41
MPC		1.2
ClinPred		0.47	T
GERP RS		2.5
Varity_R		0.34

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

LitVar

Other links and lift over

dbSNP: rs1555870287; hg19: chr19-42503322;