rs751644427

Positions:

chr11-2588756-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000218.3(KCNQ1):c.1295C>T(p.Thr432Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,430 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: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.675

Variant links:

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14196965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1295C>T	p.Thr432Ile	missense_variant	10/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1295C>T	p.Thr432Ile	missense_variant	10/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.914C>T	p.Thr305Ile	missense_variant	10/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.938C>T	p.Thr313Ile	missense_variant	10/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.755C>T	p.Thr252Ile	missense_variant	5/11			ENSP00000495806

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250850

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461430

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727018

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2016

The p.Thr432Ile variant in KCNQ1 has not been previously reported in individuals with hearing loss. This variant has been identified in 2/16204 South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs751644427); however, its frequency is not high enough to rule out a p athogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr432Ile variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.63

T;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

N;.;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0080

D;.;D

Sift4G

Uncertain

0.022

D;.;T

Polyphen

0.0020

B;.;B

Vest4

0.24

MutPred

0.16

Loss of glycosylation at T432 (P = 0.0255);.;.;

MVP

0.86

MPC

0.40

ClinPred

0.091

GERP RS

3.2

Varity_R

0.085

gMVP

0.51

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