chr19-41998880-C-A

Position:

• chr19-41998880-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.2934G>T​(p.Glu978Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 967,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0640

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=0.083054215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIK5	NM_002088.5	c.2934G>T	p.Glu978Asp	missense_variant	20/20	ENST00000593562.6	NP_002079.3
GRIK5	XM_011526862.3	c.2937G>T	p.Glu979Asp	missense_variant	20/20		XP_011525164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIK5	ENST00000593562.6	c.2934G>T	p.Glu978Asp	missense_variant	20/20	5	NM_002088.5	ENSP00000470251	P1
GRIK5	ENST00000262895.7	c.2934G>T	p.Glu978Asp	missense_variant	19/19	1		ENSP00000262895	P1
GRIK5	ENST00000454993.6	n.1811G>T		non_coding_transcript_exon_variant	9/9	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 967720 Hom.: 0 Cov.: 28 AF XY: 0.00000220 AC XY: 1 AN XY: 455034

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: 0.0000281

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000453

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

Feb 02, 2024

The c.2934G>T (p.E978D) alteration is located in exon 19 (coding exon 19) of the GRIK5 gene. This alteration results from a G to T substitution at nucleotide position 2934, causing the glutamic acid (E) at amino acid position 978 to be replaced by an aspartic acid (D). 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	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.52	.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.50	T;T
Polyphen		0.030	B;B
Vest4		0.076
MutPred		0.064		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.14
MPC		0.75
ClinPred		0.23	T
GERP RS		-0.95
Varity_R		0.20

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: rs1396223646; hg19: chr19-42503032;