dbSNP rs34516117: KCNQ1:p.Thr600Met (chr11-2847771-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1PP2BP4_ModerateBP6

The NM_000218.3(KCNQ1):c.1799C>T(p.Thr600Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,573,298 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T600T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 0.640

Publications

10 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 links:

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000218.3

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.12228444).

BP6

Variant 11-2847771-C-T is Benign according to our data. Variant chr11-2847771-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67057.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.1799C>T	p.Thr600Met	missense	Exon 16 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.1703C>T	p.Thr568Met	missense	Exon 15 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.1529C>T	p.Thr510Met	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1799C>T	p.Thr600Met	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.1418C>T	p.Thr473Met	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.1796C>T	p.Thr599Met	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000157

AC:

AN:

184516

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.0000355

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000395

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000612

AC:

AN:

1420996

Hom.:

Cov.:

AF XY:

0.0000412

AC XY:

AN XY:

703128

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

32694

American (AMR)

AF:

0.0000255

AC:

AN:

39208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25432

East Asian (EAS)

AF:

0.00

AC:

AN:

37636

South Asian (SAS)

AF:

0.00

AC:

AN:

81028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49524

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1090866

Other (OTH)

AF:

0.000119

AC:

AN:

58892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000525

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41570

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000680

ESP6500AA

AF:

0.00160

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000117

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

KCNQ1-related disorder (1)

not provided (1)

not specified (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

CardioboostArm

Benign

0.021

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.12

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.7

PhyloP100

0.64

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.72

Sift

Benign

0.11

Sift4G

Benign

0.10

Polyphen

0.81

Vest4

0.69

MVP

0.95

MPC

0.48

ClinPred

0.012

GERP RS

0.91

Varity_R

0.086

gMVP

0.82

Mutation Taster

=11/89

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over