NM_000219.6:c.162C>A

Variant names:

• chr21-34449473-G-T
• rs17173508
• NM_000219.6:c.162C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000219.6(KCNE1):​c.162C>A​(p.Phe54Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F54C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 101 uncertain in NM_000219.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

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.162C>A	p.Phe54Leu	missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.162C>A	p.Phe54Leu	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.162C>A	p.Phe54Leu	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.162C>A	p.Phe54Leu	missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.162C>A	p.Phe54Leu	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.162C>A	p.Phe54Leu	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1100726 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 558660

African (AFR) AF: 0.00 AC: 0 AN: 25218

American (AMR) AF: 0.00 AC: 0 AN: 41462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23262

East Asian (EAS) AF: 0.00 AC: 0 AN: 36132

South Asian (SAS) AF: 0.00 AC: 0 AN: 76444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 793892

Other (OTH) AF: 0.00 AC: 0 AN: 48156

GnomAD4 genome Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	0.055
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		-1.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.34		Loss of catalytic residue at F54 (P = 0.1671)
MVP		0.80
MPC		0.44
ClinPred		0.99	D
GERP RS		-6.2
Varity_R		0.36
gMVP		0.83
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17173508; hg19: chr21-35821771; COSMIC: COSV108169081;