6-73133455-G-A

Position:

• chr6-73133455-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_019842.4(KCNQ5):​c.1282G>A​(p.Ala428Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ5	NM_019842.4	c.1282G>A	p.Ala428Thr	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.1282G>A	p.Ala428Thr	missense_variant	10/14	1	NM_019842.4	ENSP00000359425.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251160 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.1339G>A (p.A447T) alteration is located in exon 11 (coding exon 11) of the KCNQ5 gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the alanine (A) at amino acid position 447 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 447 of the KCNQ5 protein (p.Ala447Thr). This variant is present in population databases (rs775391904, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KCNQ5-related conditions. ClinVar contains an entry for this variant (Variation ID: 2317635). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;.;.;T;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;T;T;T;D;T;T
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	.;.;.;.;.;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;N;N;N;.;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.060	T;T;T;T;.;T;.
Sift4G	Benign	0.36	T;T;T;T;T;T;T
Polyphen		0.024, 0.20	.;.;.;.;.;B;B
Vest4		0.75
MutPred		0.32		Gain of phosphorylation at A447 (P = 0.0195);.;.;.;Gain of phosphorylation at A447 (P = 0.0195);.;.;
MVP		0.69
MPC		1.2
ClinPred		0.51	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.69

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: rs775391904; hg19: chr6-73843178;