rs199473646

Variant names:

• chr21-34449426-T-A
• rs199473646
• NM_000219.6:c.209A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000219.6(KCNE1):​c.209A>T​(p.Lys70Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K70N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.08
• Publications: 6 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 105 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage

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.209A>T	p.Lys70Met	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.209A>T	p.Lys70Met	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.209A>T	p.Lys70Met	missense	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.209A>T	p.Lys70Met	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.209A>T	p.Lys70Met	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.209A>T	p.Lys70Met	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251404 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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442788 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 718822

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094654

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 17

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.43		Loss of ubiquitination at K70 (P = 0.0141)
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.21
gMVP		0.80
Mutation Taster		=0/100	disease causing

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: rs199473646; hg19: chr21-35821724;