11-2445103-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP5_Moderate

The NM_000218.3(KCNQ1):c.5C>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.301

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Jervell and Lange-Nielsen syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
atrial fibrillation, familial, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
short QT syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
short QT syndrome type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

PP5

Variant 11-2445103-C-G is Pathogenic according to our data. Variant chr11-2445103-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431053.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1 link	c.-358C>G		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

940006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

442668

African (AFR)

AF:

0.00

AC:

AN:

17956

American (AMR)

AF:

0.00

AC:

AN:

4150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8392

East Asian (EAS)

AF:

0.00

AC:

AN:

13234

South Asian (SAS)

AF:

0.00

AC:

AN:

20280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2112

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

828850

Other (OTH)

AF:

0.00

AC:

AN:

33302

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:1

Jul 27, 2017

Biotechnology Research Center, Pasteur Institute of Iran

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

According to the ACMG standards and guidelines, the following evidences results in the likely pathogenic variant: Not reported in ExAC and 1000G project and in more than 1000 unrelated Iranian individuals (PM2) but known disease mutation at this position (HGMD ID: CM097076, ClinVar ID: 67091) (PM5) Co segregated with the disease in the family (PP1) Missense variants in KCNQ1 gene are a common mechanism of the LQT1 disease (PP2) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

CardioboostArm

Benign

0.00044

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.34

PhyloP100

0.30

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.30

REVEL

Uncertain

0.36

Sift

Benign

0.65

Sift4G

Benign

0.53

Polyphen

0.032

Vest4

0.35

MutPred

0.24

Gain of MoRF binding (P = 0.1134);

MVP

0.90

MPC

1.2

ClinPred

0.37

GERP RS

1.7

PromoterAI

0.26

Neutral

(source)

Varity_R

0.034

gMVP

0.28

Mutation Taster

=57/43

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over