11-120819909-C-T

Variant names:

• chr11-120819909-C-T
• rs41297895
• NM_014619.5:c.500C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014619.5(GRIK4):​c.500C>T​(p.Ala167Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A167G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIK4 NM_014619.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

Genes affected

GRIK4 (HGNC:4582): (glutamate ionotropic receptor kainate type subunit 4) 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK4	NM_014619.5	c.500C>T	p.Ala167Val	missense_variant	Exon 6 of 21	ENST00000527524.8	NP_055434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK4	ENST00000527524.8	c.500C>T	p.Ala167Val	missense_variant	Exon 6 of 21	2	NM_014619.5	ENSP00000435648.2
GRIK4	ENST00000438375.2	c.500C>T	p.Ala167Val	missense_variant	Exon 5 of 20	1		ENSP00000404063.2
GRIK4	ENST00000533291.5	n.898C>T		non_coding_transcript_exon_variant	Exon 6 of 18	1
GRIK4	ENST00000638419.1	c.500C>T	p.Ala167Val	missense_variant	Exon 6 of 21	5		ENSP00000492086.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251158 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;.;N
REVEL	Pathogenic	0.67
Sift	Benign	0.033	D;.;D
Sift4G	Uncertain	0.024	D;.;D
Polyphen		1.0	D;D;D
Vest4		0.83
MutPred		0.71		Gain of methylation at K168 (P = 0.0379);Gain of methylation at K168 (P = 0.0379);Gain of methylation at K168 (P = 0.0379);
MVP		0.49
MPC		1.0
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.30
gMVP		0.79

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: rs41297895; hg19: chr11-120690618;