NM_014619.5:c.548T>G

Variant names:

• chr11-120831888-T-G
• rs1953436803
• NM_014619.5:c.548T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_014619.5(GRIK4):​c.548T>G​(p.Leu183Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GRIK4 NM_014619.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014619.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK4	NM_014619.5	MANE Select	c.548T>G	p.Leu183Arg	missense	Exon 7 of 21	NP_055434.2
	GRIK4	NM_001282470.3		c.548T>G	p.Leu183Arg	missense	Exon 6 of 20	NP_001269399.1	A0A8D9PH79
	GRIK4	NM_001440402.1		c.548T>G	p.Leu183Arg	missense	Exon 9 of 23	NP_001427331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK4	ENST00000527524.8	TSL:2 MANE Select	c.548T>G	p.Leu183Arg	missense	Exon 7 of 21	ENSP00000435648.2	Q16099
	GRIK4	ENST00000438375.2	TSL:1	c.548T>G	p.Leu183Arg	missense	Exon 6 of 20	ENSP00000404063.2	Q16099
	GRIK4	ENST00000533291.5	TSL:1	n.946T>G		non_coding_transcript_exon	Exon 7 of 18

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111904

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.63
Sift	Benign	0.37	T
Sift4G	Benign	0.67	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.50		Gain of MoRF binding (P = 0.0099)
MVP		0.97
MPC		1.6
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.91
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs1953436803; hg19: chr11-120702597;