rs1554958045

Positions:

• chr11-2445213-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000155840.12(KCNQ1):​c.115G>T​(p.Glu39Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 ENST00000155840.12 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2445213-G-T is Pathogenic according to our data. Variant chr11-2445213-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 375455.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.115G>T	p.Glu39Ter	stop_gained	1/16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.115G>T	p.Glu39Ter	stop_gained	1/15		NP_001393765.1
KCNQ1	NM_001406838.1	c.115G>T	p.Glu39Ter	stop_gained	1/11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-248G>T		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.115G>T	p.Glu39Ter	stop_gained	1/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000646564.2	c.115G>T	p.Glu39Ter	stop_gained	1/11			ENSP00000495806
KCNQ1	ENST00000496887.7	c.24-170G>T		intron_variant		5		ENSP00000434560

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 992758 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 477426

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Division of Laboratory Medicine and Clinical Genetics, Chiba University Hospital

Jan 05, 2017

The single nucleotide substitution results in a nonsense mutation. This mutation was found homozygously in the KCNQ1 gene of the proband. The proband is clinically diagnosed with Jervell and Lange-Nielsen Syndrome, because of congenital deafness, syncope and prolonged QT interval. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.72	D
MutationTaster	Benign	1.0	A
Vest4		0.53
GERP RS		2.7

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

Other links and lift over

dbSNP: rs1554958045; hg19: chr11-2466443;