rs1805128

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000219.6(KCNE1):​c.253G>A​(p.Asp85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D85E) has been classified as Uncertain significance.

• 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: 191 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005815029).
• BP6: Variant 21-34449382-C-T is Benign according to our data. Variant chr21-34449382-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|other|risk_factor. ClinVar VariationId is 13479.

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

Selected	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
	KCNE1	NM_001127668.4		c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Selected	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
	KCNE1	ENST00000399289.7	TSL:1	c.253G>A	p.Asp85Asn	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.253G>A	p.Asp85Asn	missense	Exon 2 of 2	ENSP00000416258.2

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

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00914 AC: 1110

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0122

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; other; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	3	Long QT syndrome (4)
-	-	4	not provided (6)
-	1	1	Jervell and Lange-Nielsen syndrome 2 (2)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (2)
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)
-	-	-	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
Polyphen		0.57	P
Vest4		0.22
MVP		0.89
MPC		0.19
ClinPred		0.038	T
GERP RS		4.2
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

Other links and lift over

dbSNP: rs1805128; hg19: chr21-35821680; COSMIC: COSV104640789;