chr21-34449382-C-T

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: 145 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

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		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).
	BP6Reputable source reports benign		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	Prot: NP_000210.2 UniProt:
	KCNE1 NM_001127668.4		c.253G>A p.Asp85Asn	missense	Exon 3 of 3	Prot: NP_001121140.1 UniProt:
	KCNE1 NM_001127669.4		c.253G>A p.Asp85Asn	missense	Exon 3 of 3	Prot: NP_001121141.1 UniProt:

KCNE1 NM_000219.6

MANE Select

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 4 of 4

missense

Prot: NP_000210.2UniProt: C7S316P15382

KCNE1 NM_001127668.4

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 3 of 3

missense

Prot: NP_001121140.1UniProt: P15382C7S316

KCNE1 NM_001127669.4

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 3 of 3

missense

Prot: NP_001121141.1UniProt: P15382C7S316

Ensembl Transcripts

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

KCNE1 ENST00000399286.3

TSL:1MANE Select

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 4 of 4

missense

Prot: ENSP00000382226.2UniProt: P15382

KCNE1 ENST00000399289.7

TSL:1

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 3 of 3

missense

Prot: ENSP00000382228.3UniProt: P15382

KCNE1 ENST00000416357.6

TSL:1

HGVSc / HGVSpc.253G>Ap.Asp85Asn

Exon rankExon 2 of 2

missense

Prot: ENSP00000416258.2UniProt: P15382

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:17
GnomAD2 exomes	AF: 0.00944	AC:2373	Hom:	AN:251426	Cov:
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1460688	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:17
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0114	AC:1657	Hom:17	AN:145428	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.00877	AC:114	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00346	AC:12	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00110	AC:2	Hom:	AN:1882	Cov:
Turkish Variome	AF: 0.00461	AC:31	Hom:0	AN:6720	Cov:
UK10K	AF: 0.0141	AC:107	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0152 *	169	11110	0.0148 *	261	17618

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
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
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0058	T
MetaSVM	Uncertain	-0.080	T
Mutation Taster	N/A	100/0	polymorphism
MutationAssessor	Uncertain	2.0	M
PhyloP100	Benign	3.0
popEVE	Benign	-3.5
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	N/A	0.16
VESM-3B	Benign	-6.6

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 normal

3 no calibration

4 assays found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

No calibration: 3 assays (score only).

Protein level

Functional MAVE scores for KCNE1

Cell Surface and Functional Scores for KCNE1

• Gene: KCNE1
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.919 · p.Asp85Asn (assay numbering)

Classified as

BS3 moderateFunctionally normalInvestigator-provided functional classes: normal function

+1 more calibration

BS3 very strongFunctionally normalRUO ExCALIBR calibration: BS3 Very Strong (-8)

Protein level

Trafficking scores for KCNE1 in the absence of KCNQ1

Cell Surface and Functional Scores for KCNE1

• Gene: KCNE1
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.879 · p.Asp85Asn (assay numbering)

No calibration data

This score is at approximately the 39th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

Functional MAVE scores for KCNE1

Cell Surface and Functional Scores for KCNE1

• Gene: KCNE1
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.919 · p.Asp85Asn (assay numbering)

No calibration data

This score is at approximately the 49th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

Trafficking scores for KCNE1 in the presence of KCNQ1

Cell Surface and Functional Scores for KCNE1

• Gene: KCNE1
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.910 · p.Asp85Asn (assay numbering)

No calibration data

This score is at approximately the 42th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs1805128;

hg19: chr21-35821680;

COSMIC: COSV104640789;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar