rs758346045

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-34449497-G-A
• chr21-34449497-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000219.6(KCNE1):​c.138C>T​(p.Tyr46Tyr) variant causes a synonymous 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 14)
  • Exomes 𝑓: 0.000063 (20 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B: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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 21-34449497-G-A is Benign according to our data. Variant chr21-34449497-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 527058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.322 with no splicing effect.

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>T	p.Tyr46Tyr	synonymous	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.138C>T	p.Tyr46Tyr	synonymous	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.138C>T	p.Tyr46Tyr	synonymous	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>T	p.Tyr46Tyr	synonymous	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.138C>T	p.Tyr46Tyr	synonymous	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.138C>T	p.Tyr46Tyr	synonymous	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 83868 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000199 AC: 5 AN: 251440 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000630 AC: 63 AN: 999718 Hom.: 20 Cov.: 21 AF XY: 0.0000694 AC XY: 35 AN XY: 504392

African (AFR) AF: 0.0000442 AC: 1 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: 0.0000314 AC: 1 AN: 31836

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000841 AC: 61 AN: 725272

Other (OTH) AF: 0.00 AC: 0 AN: 43216

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 83868 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 40982

African (AFR) AF: 0.00 AC: 0 AN: 19854

American (AMR) AF: 0.00 AC: 0 AN: 9246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1810

East Asian (EAS) AF: 0.00 AC: 0 AN: 2310

South Asian (SAS) AF: 0.00 AC: 0 AN: 2506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 170

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39414

Other (OTH) AF: 0.00 AC: 0 AN: 1158

Alfa AF: 0.0000947 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.5
DANN	Benign	0.58
PhyloP100		0.32
Mutation Taster		=98/2	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: rs758346045; hg19: chr21-35821795;