rs79654911

Variant names:

• chr21-34449435-C-A
• rs79654911
• NM_000219.6:c.200G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34449435-C-A
• chr21-34449435-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_000219.6(KCNE1):​c.200G>T​(p.Arg67Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.01
• Publications: 21 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_pathogenic. The variant received 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449436-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132660.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

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.200G>T	p.Arg67Leu	missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.200G>T	p.Arg67Leu	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.200G>T	p.Arg67Leu	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.200G>T	p.Arg67Leu	missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.200G>T	p.Arg67Leu	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.200G>T	p.Arg67Leu	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251394 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000285 AC: 4 AN: 1404598 Hom.: 0 Cov.: 26 AF XY: 0.00000428 AC XY: 3 AN XY: 701304

African (AFR) AF: 0.00 AC: 0 AN: 32492

American (AMR) AF: 0.00 AC: 0 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 84776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1060726

Other (OTH) AF: 0.00 AC: 0 AN: 58556

GnomAD4 genome Cov.: 17

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.55	P
Vest4		0.93
MutPred		0.79		Loss of disorder (P = 0.0565)
MVP		0.96
MPC		0.38
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs79654911; hg19: chr21-35821733;