rs1805128

Variant names:

• chr21-34449382-C-T
• rs1805128
• NM_000219.6:c.253G>A
• KCNE1 p.Asp85Asn

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingBP6_Strong

The NM_000219.6(KCNE1):c.253G>A (p.Asp85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. No reliable population frequency data is available for this variant in the gnomAD database. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D85A: unknown significance (ClinVar VariationId 3374448); p.D85= (synonymous): Likely_benign (ClinVar VariationId 1793098, 1 star); p.D85E: unknown significance (ClinVar VariationId 3374452); p.D85E: Uncertain_significance (ClinVar VariationId 3374451, 1 star); p.D85G: unknown significance (ClinVar VariationId 3374449); p.D85H: unknown significance (ClinVar VariationId 3374446); p.D85V: unknown significance (ClinVar VariationId 3374450); p.D85Y: unknown significance (ClinVar VariationId 3374447) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:2 U:2 B:14 O:5
• Conservation: PhyloP100: 2.98
• Publications: 192 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: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: G2P, 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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -3 points.

• PM1: UniProt domain with ≥4 pathogenic missense and OR ≥ 2 vs. background — moderate hotspot (PM1 supporting); In-domain: 17 pathogenic, 20 benign rare missense variants (OR vs. background: 4.3).; ±8 AA neighbourhood: 1 pathogenic, 1 benign (OR vs. background: 5.0).
• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (13/15 total B/LB).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	NM_000219.6	MANE Select	c.253G>A	p.Asp85Asn	missense	Exon 4 of 4	NP_000210.2	C7S316
	KCNE1	NM_001127668.4		c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	NP_001121141.1	P15382

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.253G>A	p.Asp85Asn	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.253G>A	p.Asp85Asn	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.00944 AC: 2373 AN: 251426 AF XY: 0.00957

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00549

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00879

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726712

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110896

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 17

Alfa AF: 0.0117 Hom.: 16

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0122

Local populations

Turkish Variome AF: 0.00461 AC: 31 AN: 6720 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (7)
1	-	3	Long QT syndrome (4)
-	1	1	Jervell and Lange-Nielsen syndrome 2 (2)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome 2/5, digenic (1)
-	-	1	Long QT syndrome 5 (2)
-	1	-	Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)
-	-	-	Congenital long QT syndrome (1)
-	-	-	Long QT syndrome 5, acquired, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0058	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.33
Sift	Benign	0.034	D
Sift4G	Benign	0.068	T
Varity_R		0.16
gMVP		0.84
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1805128;

hg19: chr21-35821680;

COSMIC: COSV104640789;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar