21-34449639-G-T

Variant names:

• chr21-34449639-G-T
• rs191334763
• NM_000219.6:c.-5C>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.-5C>A variant causes a 5 prime UTR 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 13)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.675
• 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 21-34449639-G-T is Benign according to our data. Variant chr21-34449639-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504745.

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.-5C>A		5_prime_UTR	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.-5C>A		5_prime_UTR	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.-5C>A		5_prime_UTR	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.-5C>A		5_prime_UTR	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.-5C>A		5_prime_UTR	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.-5C>A		5_prime_UTR	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 6 AN: 96352 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250842 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000925

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000192 AC: 14 AN: 728066 Hom.: 0 Cov.: 10 AF XY: 0.0000160 AC XY: 6 AN XY: 375730

African (AFR) AF: 0.00 AC: 0 AN: 17918

American (AMR) AF: 0.00 AC: 0 AN: 32666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17894

East Asian (EAS) AF: 0.000398 AC: 13 AN: 32636

South Asian (SAS) AF: 0.00 AC: 0 AN: 60820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3368

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 487114

Other (OTH) AF: 0.0000282 AC: 1 AN: 35442

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000622 AC: 6 AN: 96448 Hom.: 0 Cov.: 13 AF XY: 0.0000860 AC XY: 4 AN XY: 46504

African (AFR) AF: 0.00 AC: 0 AN: 24320

American (AMR) AF: 0.00 AC: 0 AN: 10244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2142

East Asian (EAS) AF: 0.00212 AC: 6 AN: 2832

South Asian (SAS) AF: 0.00 AC: 0 AN: 2870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44274

Other (OTH) AF: 0.00 AC: 0 AN: 1318

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		0.68
Varity_R		0.12
Mutation Taster		=294/6	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: rs191334763; hg19: chr21-35821937; COSMIC: COSV100492422;