21-34446770-T-C

Variant names:

• chr21-34446770-T-C
• rs913676929
• NM_000219.6:c.*2475A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000219.6(KCNE1):​c.*2475A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.00016 (5 hom., cov: 11)
• Consequence: KCNE1 NM_000219.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.77
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.*2475A>G		3_prime_UTR	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.*2475A>G		3_prime_UTR	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.*2475A>G		3_prime_UTR	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.*2475A>G		3_prime_UTR	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.*2475A>G		3_prime_UTR	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000432085.5	TSL:1	c.*2475A>G		3_prime_UTR	Exon 3 of 3	ENSP00000412498.1	P15382

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 13 AN: 82426 Hom.: 5 Cov.: 11

Gnomad AFR AF: 0.00

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: 0.000339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000243

Gnomad OTH AF: 0.00177

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.000158 AC: 13 AN: 82426 Hom.: 5 Cov.: 11 AF XY: 0.000150 AC XY: 6 AN XY: 40106

African (AFR) AF: 0.00 AC: 0 AN: 22066

American (AMR) AF: 0.00 AC: 0 AN: 8610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2018

East Asian (EAS) AF: 0.00 AC: 0 AN: 2500

South Asian (SAS) AF: 0.00 AC: 0 AN: 2600

European-Finnish (FIN) AF: 0.000339 AC: 2 AN: 5900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.000243 AC: 9 AN: 36962

Other (OTH) AF: 0.00177 AC: 2 AN: 1128

Alfa AF: 0.000169 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Jervell and Lange-Nielsen syndrome 2 (1)
-	1	-	Long QT syndrome 5 (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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.37
PhyloP100		-1.8

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: rs913676929; hg19: chr21-35819068;