chr19-41999253-G-C

Position:

• chr19-41999253-G-C

Variant summary

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

The NM_002088.5(GRIK5):​c.2561C>G​(p.Ser854Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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=0.1731922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIK5	NM_002088.5	c.2561C>G	p.Ser854Cys	missense_variant	20/20	ENST00000593562.6	NP_002079.3
GRIK5	XM_011526862.3	c.2564C>G	p.Ser855Cys	missense_variant	20/20		XP_011525164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIK5	ENST00000593562.6	c.2561C>G	p.Ser854Cys	missense_variant	20/20	5	NM_002088.5	ENSP00000470251	P1
GRIK5	ENST00000262895.7	c.2561C>G	p.Ser854Cys	missense_variant	19/19	1		ENSP00000262895	P1
GRIK5	ENST00000454993.6	n.1438C>G		non_coding_transcript_exon_variant	9/9	1
GRIK5	ENST00000602210.1	n.379C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.2561C>G (p.S854C) alteration is located in exon 19 (coding exon 19) of the GRIK5 gene. This alteration results from a C to G substitution at nucleotide position 2561, causing the serine (S) at amino acid position 854 to be replaced by a cysteine (C). 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	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.16
Sift	Benign	0.052	T;.
Sift4G	Benign	0.076	T;T
Polyphen		0.0050	B;B
Vest4		0.39
MutPred		0.33		Loss of phosphorylation at S854 (P = 0.0199);Loss of phosphorylation at S854 (P = 0.0199);
MVP		0.53
MPC		0.81
ClinPred		0.40	T
GERP RS		2.6
Varity_R		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-42503405;