21-34450274-A-G

Variant names:

• chr21-34450274-A-G
• rs1547356
• NM_000219.6:c.-50-590T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000219.6(KCNE1):​c.-50-590T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.896
• Publications: 3 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	NM_000219.6	MANE Select	c.-50-590T>C		intron	N/A	NP_000210.2
	KCNE1	NM_001127668.4		c.-50-590T>C		intron	N/A	NP_001121140.1
	KCNE1	NM_001127669.4		c.-50-590T>C		intron	N/A	NP_001121141.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.-50-590T>C		intron	N/A	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.-50-590T>C		intron	N/A	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.-50-590T>C		intron	N/A	ENSP00000416258.2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 554 AN: 43596 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00930

Gnomad EAS AF: 0.0134

Gnomad SAS AF: 0.0150

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.00709

Gnomad OTH AF: 0.0170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0127 AC: 552 AN: 43606 Hom.: 20 Cov.: 0 AF XY: 0.0115 AC XY: 240 AN XY: 20894

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

African (AFR) AF: 0.0351 AC: 180 AN: 5126

American (AMR) AF: 0.0163 AC: 85 AN: 5216

Ashkenazi Jewish (ASJ) AF: 0.00930 AC: 9 AN: 968

East Asian (EAS) AF: 0.0134 AC: 10 AN: 746

South Asian (SAS) AF: 0.0142 AC: 17 AN: 1196

European-Finnish (FIN) AF: 0.0151 AC: 57 AN: 3784

Middle Eastern (MID) AF: 0.0217 AC: 2 AN: 92

European-Non Finnish (NFE) AF: 0.00710 AC: 182 AN: 25650

Other (OTH) AF: 0.0170 AC: 10 AN: 588

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.712 Hom.: 56260

Asia WGS AF: 0.827 AC: 2878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1547356; hg19: chr21-35822572;