NM_000219.6:c.200G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_000219.6(KCNE1):​c.200G>A​(p.Arg67His) variant causes a missense change. The variant allele was found at a frequency of 0.0000903 in 1,538,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: 𝑓 0.00018 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 O:1
• 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: Uncertain_significance. The variant received 4 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, 0.935

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>A	p.Arg67His	missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.200G>A	p.Arg67His	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.200G>A	p.Arg67His	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>A	p.Arg67His	missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.200G>A	p.Arg67His	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.200G>A	p.Arg67His	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 24 AN: 134000 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000233

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000566

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251394 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000819 AC: 115 AN: 1404590 Hom.: 0 Cov.: 26 AF XY: 0.0000870 AC XY: 61 AN XY: 701296

African (AFR) AF: 0.0000923 AC: 3 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: 0.0000254 AC: 1 AN: 39354

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84776

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.000101 AC: 107 AN: 1060720

Other (OTH) AF: 0.0000512 AC: 3 AN: 58554

GnomAD4 genome AF: 0.000179 AC: 24 AN: 134000 Hom.: 0 Cov.: 17 AF XY: 0.000201 AC XY: 13 AN XY: 64662

African (AFR) AF: 0.000333 AC: 12 AN: 36010

American (AMR) AF: 0.0000755 AC: 1 AN: 13240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3100

East Asian (EAS) AF: 0.000233 AC: 1 AN: 4298

South Asian (SAS) AF: 0.00 AC: 0 AN: 3920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000147 AC: 9 AN: 61292

Other (OTH) AF: 0.000566 AC: 1 AN: 1768

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Long QT syndrome (2)
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Jervell and Lange-Nielsen syndrome 2 (1)
1	-	-	Long QT syndrome 5 (1)
-	1	-	Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)
-	1	-	not specified (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		0.48
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.83
Mutation Taster		=2/98	disease causing

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;