chr11-2768837-A-AGC

Position:

• chr11-2768837-A-AGC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000155840.12(KCNQ1):​c.1515-7_1515-6insGC variant causes a splice region, splice polypyrimidine tract, intron 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 ENST00000155840.12 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1515-7_1515-6insGC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1515-7_1515-6insGC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1134-7_1134-6insGC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1158-7_1158-6insGC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.975-7_975-6insGC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ1-related disease. In summary, this is a novel intronic change with uncertain impact on mRNA splicing. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. This sequence change falls in intron 11 of the KCNQ1 mRNA. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554919460; hg19: chr11-2790067;