chr19-41999247-C-A

Position:

• chr19-41999247-C-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.2567G>T​(p.Arg856Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,372,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R856H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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=0.1879521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK5	NM_002088.5	c.2567G>T	p.Arg856Leu	missense_variant	20/20	ENST00000593562.6
GRIK5	XM_011526862.3	c.2570G>T	p.Arg857Leu	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK5	ENST00000593562.6	c.2567G>T	p.Arg856Leu	missense_variant	20/20	5	NM_002088.5	P1
GRIK5	ENST00000262895.7	c.2567G>T	p.Arg856Leu	missense_variant	19/19	1		P1
GRIK5	ENST00000454993.6	n.1444G>T		non_coding_transcript_exon_variant	9/9	1
GRIK5	ENST00000602210.1	n.385G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372456 Hom.: 0 Cov.: 33 AF XY: 0.00000148 AC XY: 1 AN XY: 677192

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: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.93	N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.031
Sift	Uncertain	0.025	D;.
Sift4G	Uncertain	0.043	D;D
Polyphen		0.49	P;P
Vest4		0.34
MutPred		0.31		Loss of methylation at K857 (P = 0.0469);Loss of methylation at K857 (P = 0.0469);
MVP		0.24
MPC		1.3
ClinPred		0.57	D
GERP RS		3.0
Varity_R		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42503399;