21-34449497-G-T

Variant names:

• chr21-34449497-G-T
• rs758346045
• NM_000219.6:c.138C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000219.6(KCNE1):​c.138C>A​(p.Tyr46*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 999,724 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y46Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: KCNE1 NM_000219.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.322
• Publications: 1 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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-34449497-G-T is Pathogenic according to our data. Variant chr21-34449497-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 547162.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	NM_000219.6	MANE Select	c.138C>A	p.Tyr46*	stop_gained	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.138C>A	p.Tyr46*	stop_gained	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.138C>A	p.Tyr46*	stop_gained	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.138C>A	p.Tyr46*	stop_gained	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.138C>A	p.Tyr46*	stop_gained	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.138C>A	p.Tyr46*	stop_gained	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251440 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 3 AN: 999724 Hom.: 0 Cov.: 21 AF XY: 0.00000595 AC XY: 3 AN XY: 504396

African (AFR) AF: 0.00 AC: 0 AN: 22602

American (AMR) AF: 0.00 AC: 0 AN: 38364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20862

East Asian (EAS) AF: 0.00 AC: 0 AN: 31836

South Asian (SAS) AF: 0.0000294 AC: 2 AN: 67958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00000138 AC: 1 AN: 725276

Other (OTH) AF: 0.00 AC: 0 AN: 43218

GnomAD4 genome Cov.: 14

Alfa AF: 0.0000237 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Jervell and Lange-Nielsen syndrome 2 (1)
1	-	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		0.32
Vest4		0.91
GERP RS		1.4
Mutation Taster		=0/200	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: rs758346045; hg19: chr21-35821795;