11-2444984-GC-GCC

Variant names:

• chr11-2444984-G-GC
• rs944443085
• ENST00000713725.1:c.-109dupC

Variant summary

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

The ENST00000713725.1(KCNQ1):​c.-109dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 547,600 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KCNQ1 ENST00000713725.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.943
• Publications: 0 publications found

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
• 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
• long QT syndrome 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000713725.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.-115_-114insC		upstream_gene	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.-115_-114insC		upstream_gene	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.-477_-476insC		upstream_gene	N/A	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000713725.1		c.-109dupC		5_prime_UTR	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5
	KCNQ1	ENST00000496887.7	TSL:5	c.23+282dupC		intron	N/A	ENSP00000434560.2	E9PPZ0
	KCNQ1	ENST00000713724.1		n.-109dupC		non_coding_transcript_exon	Exon 1 of 16	ENSP00000519028.1	A0AAQ5BGV1

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146538 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 6 AN: 401062 Hom.: 0 Cov.: 5 AF XY: 0.0000158 AC XY: 3 AN XY: 189388

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7448

American (AMR) AF: 0.00 AC: 0 AN: 938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2698

East Asian (EAS) AF: 0.00 AC: 0 AN: 2086

South Asian (SAS) AF: 0.00 AC: 0 AN: 8060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 838

European-Non Finnish (NFE) AF: 0.0000165 AC: 6 AN: 363774

Other (OTH) AF: 0.00 AC: 0 AN: 13556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0153586), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146538 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71258

African (AFR) AF: 0.00 AC: 0 AN: 40792

American (AMR) AF: 0.00 AC: 0 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65862

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.94

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs944443085; hg19: chr11-2466214;