chr6-73133459-G-T

Variant names:

• chr6-73133459-G-T
• rs1135401957
• NM_019842.4:c.1286G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 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:40323): (KCNQ5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
KCNQ5	NM_019842.4	c.1286G>T	p.Ser429Ile	missense_variant	Exon 10 of 14	ENST00000370398.6	NP_062816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6	c.1286G>T	p.Ser429Ile	missense_variant	Exon 10 of 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

Dec 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change resulted in slowed activation kinetics with no effect on deactivation or channel expression (PMID: 28669405). 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). This variant is not present in population databases (ExAC no frequency). 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. -

Intellectual disability, autosomal dominant 46 Pathogenic:1

Apr 26, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;