11-2445250-A-ACGCGCCCATCGCGCCCAT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000218.3(KCNQ1):c.168_169insATCGCGCCCATCGCGCCC(p.Pro56_Gly57insIleAlaProIleAlaPro) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000674 in 148,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
• Consequence: KCNQ1 NM_000218.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.203

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.168_169insATCGCGCCCATCGCGCCC	p.Pro56_Gly57insIleAlaProIleAlaPro	inframe_insertion	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.168_169insATCGCGCCCATCGCGCCC	p.Pro56_Gly57insIleAlaProIleAlaPro	inframe_insertion	1/15
KCNQ1	NM_001406838.1	c.168_169insATCGCGCCCATCGCGCCC	p.Pro56_Gly57insIleAlaProIleAlaPro	inframe_insertion	1/11
KCNQ1	NM_001406837.1	c.-195_-194insATCGCGCCCATCGCGCCC		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.168_169insATCGCGCCCATCGCGCCC	p.Pro56_Gly57insIleAlaProIleAlaPro	inframe_insertion	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.168_169insATCGCGCCCATCGCGCCC	p.Pro56_Gly57insIleAlaProIleAlaPro	inframe_insertion	1/11
KCNQ1	ENST00000496887.7	c.24-117_24-116insATCGCGCCCATCGCGCCC		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148266 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148266 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72284

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The c.168_169ins18 variant (also known as p.P56_G57insIAPIAP), located in coding exon 1 of the KCNQ1 gene, results from an in-frame 18 nucleotide insertion at nucleotide positions 168 to 169. This results in the insertion of 6 extra residues between codons 56 and 57. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: rs397515877; hg19: chr11-2466480;