chr11-2847842-ACCCCCGGCAGCGGCGGCC-A

Variant names:

• chr11-2847842-ACCCCCGGCAGCGGCGGCC-A
• rs397508102
• NM_000218.3:c.1876_1893delGGCAGCGGCGGCCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000218.3(KCNQ1):​c.1876_1893delGGCAGCGGCGGCCCCCCC​(p.Gly626_Pro631del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,302 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 2.20
• Publications: 1 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1876_1893delGGCAGCGGCGGCCCCCCC	p.Gly626_Pro631del	conservative_inframe_deletion	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	c.1876_1893delGGCAGCGGCGGCCCCCCC	p.Gly626_Pro631del	conservative_inframe_deletion	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417302 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 700868

African (AFR) AF: 0.00 AC: 0 AN: 32508

American (AMR) AF: 0.00 AC: 0 AN: 38968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25364

East Asian (EAS) AF: 0.0000806 AC: 3 AN: 37232

South Asian (SAS) AF: 0.00 AC: 0 AN: 80770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088886

Other (OTH) AF: 0.00 AC: 0 AN: 58628

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiac arrhythmia Uncertain:1

May 07, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the KCNQ1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one family affected with long QT syndrome (PMID: 14731347, 27707468). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Long QT syndrome 1 Other:1

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=38/162	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs397508102; hg19: chr11-2869072;