6-73133459-G-T

Position:

• chr6-73133459-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_019842.4(KCNQ5):​c.1286G>T​(p.Ser429Ile) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.52

Genes affected

KCNQ5 (HGNC:6299): (potassium voltage-gated channel subfamily Q member 5) This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

KCNQ5-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ5. . Gene score misZ 3.3177 (greater than the threshold 3.09). Trascript score misZ 3.1292 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 46.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant 6-73133459-G-T is Pathogenic according to our data. Variant chr6-73133459-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 431387.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ5	NM_019842.4	c.1286G>T	p.Ser429Ile	missense_variant	10/14	ENST00000370398.6	NP_062816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6	c.1286G>T	p.Ser429Ile	missense_variant	10/14	1	NM_019842.4	ENSP00000359425.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2017

This sequence change replaces serine with isoleucine at codon 448 of the KCNQ5 protein (p.Ser448Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with epileptic encephalopathy (PMID: 28669405). ClinVar contains an entry for this variant (Variation ID: 431387). Experimental studies have shown that this missense change resulted in slowed activation kinetics with no effect on deactivation or channel expression (PMID: 28669405). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability, autosomal dominant 46 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;.;T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	2.9	.;.;.;.;.;M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0080	D;D;D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D
Polyphen		0.38, 0.73	.;.;.;.;.;B;P
Vest4		0.81
MutPred		0.35		Loss of phosphorylation at S448 (P = 0.0017);.;.;.;Loss of phosphorylation at S448 (P = 0.0017);.;.;
MVP		0.87
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.75
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1135401957; hg19: chr6-73843182; COSMIC: COSV105208711; COSMIC: COSV105208711;