rs754731040

Variant names:

• chr21-34449460-G-A
• rs754731040
• NM_000219.6:c.175C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34449460-G-A
• chr21-34449460-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000219.6(KCNE1):​c.175C>T​(p.Leu59Leu) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 21-34449460-G-A is Benign according to our data. Variant chr21-34449460-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 237230.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.175C>T	p.Leu59Leu	synonymous	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.175C>T	p.Leu59Leu	synonymous	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.175C>T	p.Leu59Leu	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.175C>T	p.Leu59Leu	synonymous	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.175C>T	p.Leu59Leu	synonymous	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.175C>T	p.Leu59Leu	synonymous	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.72e-7 AC: 1 AN: 1146516 Hom.: 0 Cov.: 19 AF XY: 0.00000172 AC XY: 1 AN XY: 581128

African (AFR) AF: 0.00 AC: 0 AN: 26596

American (AMR) AF: 0.00 AC: 0 AN: 41788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23696

East Asian (EAS) AF: 0.00 AC: 0 AN: 36784

South Asian (SAS) AF: 0.00 AC: 0 AN: 77570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833084

Other (OTH) AF: 0.0000200 AC: 1 AN: 49888

GnomAD4 genome Cov.: 17

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		1.8

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: rs754731040; hg19: chr21-35821758;