rs727503101

Variant names:

• chr21-34449461-G-C
• rs727503101
• NM_000219.6:c.174C>G

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.174C>G​(p.Thr58Thr) 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. T58T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0280
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.52).
• BP6: Variant 21-34449461-G-C is Benign according to our data. Variant chr21-34449461-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 163728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.028 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.174C>G	p.Thr58Thr	synonymous	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.174C>G	p.Thr58Thr	synonymous	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.174C>G	p.Thr58Thr	synonymous	Exon 3 of 3	NP_001121141.1	C7S316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.174C>G	p.Thr58Thr	synonymous	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.174C>G	p.Thr58Thr	synonymous	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.174C>G	p.Thr58Thr	synonymous	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.0000172 AC: 2 AN: 116432 Hom.: 0 Cov.: 17

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: 0.0000372

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251418 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000758 AC: 87 AN: 1147528 Hom.: 0 Cov.: 19 AF XY: 0.0000722 AC XY: 42 AN XY: 581558

African (AFR) AF: 0.00 AC: 0 AN: 26614

American (AMR) AF: 0.00 AC: 0 AN: 41782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23692

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 77620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.000102 AC: 85 AN: 834026

Other (OTH) AF: 0.0000401 AC: 2 AN: 49890

GnomAD4 genome AF: 0.0000172 AC: 2 AN: 116432 Hom.: 0 Cov.: 17 AF XY: 0.0000178 AC XY: 1 AN XY: 56054

African (AFR) AF: 0.00 AC: 0 AN: 30504

American (AMR) AF: 0.00 AC: 0 AN: 11662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2678

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 3306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.0000372 AC: 2 AN: 53832

Other (OTH) AF: 0.00 AC: 0 AN: 1552

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.3
DANN	Benign	0.66
PhyloP100		-0.028
Mutation Taster		=99/1	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: rs727503101; hg19: chr21-35821759;