Variant 6-72622238-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_019842.4(KCNQ5):c.49T>C(p.Trp17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,244,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

KCNQ5
NM_019842.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Variant links:

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 links:

KCNQ5 (HGNC:):

KCNQ5 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.49T>C	p.Trp17Arg	missense_variant	1/14	ENST00000370398.6	NP_062816.2	Q9NR82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6 linkuse as main transcript	c.49T>C	p.Trp17Arg	missense_variant	1/14	1	NM_019842.4	ENSP00000359425.1		Q9NR82-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1092974

Hom.:

Cov.:

AF XY:

0.00000193

AC XY:

AN XY:

517422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 46

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 21, 2019

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.34

.;.;.;T;.;T;.;T;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.66

T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.5

L;L;.;.;.;.;.;L;L;L

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-3.3

D;.;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;.;D;D;D;D;D;D;D;.

Sift4G

Benign

0.36

T;T;T;T;T;T;T;T;T;T

Polyphen

0.74, 0.98, 0.83

.;.;.;.;.;.;.;P;D;P

Vest4

0.44

MutPred

0.46

Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);Gain of methylation at W17 (P = 0.0071);

MVP

0.56

MPC

3.3

ClinPred

0.99

GERP RS

3.9

Varity_R

0.67

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over