21-34449380-ATC-GTT

Variant names:

• chr21-34449380-ATC-GTT
• NM_000219.6:c.253_255delGATinsAAC
• KCNE1 p.Asp85Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM1_Supporting

The NM_000219.6(KCNE1):c.253_255delGATinsAAC (p.Asp85Asn) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. No reliable population frequency data is available for this variant in the gnomAD database. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.D85N: Conflicting_classifications_of_pathogenicity|other|risk_factor (ClinVar VariationId 13479); 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)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91
• 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: 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: Uncertain_significance. The variant received 1 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).

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.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: NP_000210.2 UniProt:
	KCNE1 NM_001127668.4		c.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: NP_001121140.1 UniProt:
	KCNE1 NM_001127669.4		c.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: NP_001121141.1 UniProt:

KCNE1 NM_000219.6

MANE Select

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

missense

Prot: NP_000210.2UniProt: C7S316P15382

KCNE1 NM_001127668.4

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

missense

Prot: NP_001121140.1UniProt: P15382C7S316

KCNE1 NM_001127669.4

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

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.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: ENSP00000382226.2 UniProt:
	KCNE1 ENST00000399289.7	TSL:1	c.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: ENSP00000382228.3 UniProt:
	KCNE1 ENST00000416357.6	TSL:1	c.253_255delGATinsAAC p.Asp85Asn	missense	N/A	Prot: ENSP00000416258.2 UniProt:

KCNE1 ENST00000399286.3

TSL:1MANE Select

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

missense

Prot: ENSP00000382226.2UniProt: P15382

KCNE1 ENST00000399289.7

TSL:1

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

missense

Prot: ENSP00000382228.3UniProt: P15382

KCNE1 ENST00000416357.6

TSL:1

HGVSc / HGVSpc.253_255delGATinsAACp.Asp85Asn

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:17
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:17

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr21-35821678;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar