21-34449393-T-C

Variant names:

• chr21-34449393-T-C
• rs199473359
• NM_000219.6:c.242A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000219.6(KCNE1):​c.242A>G​(p.Tyr81Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. Y81S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 18)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 6.81
• Publications: 10 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 108 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

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.242A>G	p.Tyr81Cys	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.242A>G	p.Tyr81Cys	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.242A>G	p.Tyr81Cys	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.242A>G	p.Tyr81Cys	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.242A>G	p.Tyr81Cys	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.242A>G	p.Tyr81Cys	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251436 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 18

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.68		Loss of phosphorylation at Y81 (P = 0.0215)
MVP		0.93
MPC		0.48
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.40
gMVP		0.96
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: rs199473359; hg19: chr21-35821691;