Variant 1-40784236-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004700.4(KCNQ4):c.143T>A(p.Leu48Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000537 in 1,304,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33782753).

BS2

High AC in GnomAdExome4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.143T>A	p.Leu48Gln	missense_variant	Exon 1 of 14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8
KCNQ4	NM_172163.3 link	c.143T>A	p.Leu48Gln	missense_variant	Exon 1 of 13		NP_751895.1	P56696-2B3KQH8
KCNQ4	XM_047434057.1 link	c.143T>A	p.Leu48Gln	missense_variant	Exon 1 of 13		XP_047290013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10 link	c.143T>A	p.Leu48Gln	missense_variant	Exon 1 of 14	1	NM_004700.4	ENSP00000262916.6		P56696-1
KCNQ4	ENST00000509682.6 link	c.143T>A	p.Leu48Gln	missense_variant	Exon 1 of 13	5		ENSP00000423756.2		P56696-2

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

148928

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:

0.0000299

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1155078

Hom.:

Cov.:

AF XY:

0.0000533

AC XY:

AN XY:

562566

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:

0.0000694

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000134

AC:

AN:

148928

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72638

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:

0.0000299

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143T>A (p.L48Q) alteration is located in exon 1 (coding exon 1) of the KCNQ4 gene. This alteration results from a T to A substitution at nucleotide position 143, causing the leucine (L) at amino acid position 48 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.68

.;T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

.;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.10

.;T;T

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

0.79

P;P;P

Vest4

0.22, 0.29

MutPred

0.27

Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);

MVP

0.74

MPC

2.3

ClinPred

0.84

GERP RS

1.9

Varity_R

0.24

gMVP

0.54

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