dbSNP rs11601907: KCNQ1:p.Tyr662* (chr11-2847958-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_000218.3(KCNQ1):c.1986C>A(p.Tyr662*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y662Y) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.57

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0222 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.1986C>A	p.Tyr662*	stop_gained	Exon 16 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.1986C>A	p.Tyr662*	stop_gained	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412468

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32456

American (AMR)

AF:

0.00

AC:

AN:

38698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25040

East Asian (EAS)

AF:

0.00

AC:

AN:

37296

South Asian (SAS)

AF:

0.00

AC:

AN:

80496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48866

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085566

Other (OTH)

AF:

0.00

AC:

AN:

58366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.25

PhyloP100

-2.6

Vest4

0.84

GERP RS

-2.3

Mutation Taster

=6/194

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over