21-34449496-C-G

Variant names:

• chr21-34449496-C-G
• rs199473353
• NM_000219.6:c.139G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000219.6(KCNE1):​c.139G>C​(p.Val47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. V47G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 14)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 100 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2440171).

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.139G>C	p.Val47Leu	missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.139G>C	p.Val47Leu	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.139G>C	p.Val47Leu	missense	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.139G>C	p.Val47Leu	missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.139G>C	p.Val47Leu	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.139G>C	p.Val47Leu	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 14

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.56
Sift	Benign	0.33	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.29
MutPred		0.25		Loss of sheet (P = 0.0457)
MVP		0.75
MPC		0.089
ClinPred		0.25	T
GERP RS		1.7
Varity_R		0.029
gMVP		0.60
Mutation Taster		=92/8	polymorphism

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: rs199473353; hg19: chr21-35821794;