19-41999044-G-A

Position:

• chr19-41999044-G-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.2770C>T​(p.Pro924Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,088,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000028 (0 hom.)
• Consequence: GRIK5 NM_002088.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.711

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=0.09733838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK5	NM_002088.5	c.2770C>T	p.Pro924Ser	missense_variant	20/20	ENST00000593562.6
GRIK5	XM_011526862.3	c.2773C>T	p.Pro925Ser	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK5	ENST00000593562.6	c.2770C>T	p.Pro924Ser	missense_variant	20/20	5	NM_002088.5	P1
GRIK5	ENST00000262895.7	c.2770C>T	p.Pro924Ser	missense_variant	19/19	1		P1
GRIK5	ENST00000454993.6	n.1647C>T		non_coding_transcript_exon_variant	9/9	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1088102 Hom.: 0 Cov.: 29 AF XY: 0.00000382 AC XY: 2 AN XY: 523010

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: 0.0000706

GnomAD4 genome Cov.: 31

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

Aug 28, 2023

The c.2770C>T (p.P924S) alteration is located in exon 19 (coding exon 19) of the GRIK5 gene. This alteration results from a C to T substitution at nucleotide position 2770, causing the proline (P) at amino acid position 924 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.056	T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.54	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.85	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.48	N;.
REVEL	Benign	0.024
Sift	Benign	0.46	T;.
Sift4G	Benign	0.55	T;T
Polyphen		0.13	B;B
Vest4		0.071
MutPred		0.17		Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);
MVP		0.36
MPC		0.85
ClinPred		0.060	T
GERP RS		-0.24
Varity_R		0.070

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: chr19-42503196;