11-120660387-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014619.5(GRIK4):c.69C>G(p.His23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,466 control chromosomes in the GnomAD database, including 33 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (17 hom.)
• Consequence: GRIK4 NM_014619.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004822135).
• BP6: Variant 11-120660387-C-G is Benign according to our data. Variant chr11-120660387-C-G is described in ClinVar as [Benign]. Clinvar id is 784221.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00779 (1186/152328) while in subpopulation AFR AF= 0.0273 (1134/41576). AF 95% confidence interval is 0.026. There are 16 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK4	NM_014619.5	c.69C>G	p.His23Gln	missense_variant	3/21	ENST00000527524.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK4	ENST00000527524.8	c.69C>G	p.His23Gln	missense_variant	3/21	2	NM_014619.5	P1

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1189 AN: 152210 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00195 AC: 488 AN: 250480 Hom.: 7 AF XY: 0.00145 AC XY: 197 AN XY: 135506

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000775 AC: 1132 AN: 1460138 Hom.: 17 Cov.: 31 AF XY: 0.000610 AC XY: 443 AN XY: 726518

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152328 Hom.: 16 Cov.: 33 AF XY: 0.00729 AC XY: 543 AN XY: 74496

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.00899

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Benign	0.88
DEOGEN2	Benign	0.061	T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.63	D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.76	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Benign	0.23
Sift	Benign	0.47	T;.;T
Sift4G	Benign	0.59	T;.;T
Polyphen		0.0010	B;B;B
Vest4		0.65
MutPred		0.36		Loss of catalytic residue at L25 (P = 0.057);Loss of catalytic residue at L25 (P = 0.057);Loss of catalytic residue at L25 (P = 0.057);
MVP		0.57
MPC		0.53
ClinPred		0.0096	T
GERP RS		3.6
Varity_R		0.20
gMVP		0.31

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: rs116098730; hg19: chr11-120531096;