rs1131691762

Variant names:

• chr21-34449622-T-TA
• rs1131691762
• NM_000219.6:c.12dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000219.6(KCNE1):​c.12dupT​(p.Asn5fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S4S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -4.43
• Publications: 2 publications found

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
• PP5: Variant 21-34449622-T-TA is Pathogenic according to our data. Variant chr21-34449622-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 430060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. 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
	KCNE1	NM_000219.6	MANE Select	c.12dupT	p.Asn5fs	frameshift	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.12dupT	p.Asn5fs	frameshift	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.12dupT	p.Asn5fs	frameshift	Exon 3 of 3	NP_001121141.1	C7S316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.12dupT	p.Asn5fs	frameshift	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.12dupT	p.Asn5fs	frameshift	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.12dupT	p.Asn5fs	frameshift	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251142 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000263 AC: 2 AN: 761030 Hom.: 0 Cov.: 10 AF XY: 0.00000254 AC XY: 1 AN XY: 392938

African (AFR) AF: 0.00 AC: 0 AN: 18842

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18726

East Asian (EAS) AF: 0.00 AC: 0 AN: 33072

South Asian (SAS) AF: 0.00 AC: 0 AN: 62894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3670

European-Non Finnish (NFE) AF: 0.00000392 AC: 2 AN: 509802

Other (OTH) AF: 0.00 AC: 0 AN: 36614

GnomAD4 genome Cov.: 13

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Jervell and Lange-Nielsen syndrome 2 (1)
1	-	-	Long QT syndrome (1)
1	-	-	Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1131691762; hg19: chr21-35821920;