rs17173510

Variant names:

• chr21-34449551-C-T
• rs17173510
• NM_000219.6:c.84G>A
• KCNE1 p.Ser28Ser

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000219.6(KCNE1):​c.84G>A​(p.Ser28Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 967,632 control chromosomes in the GnomAD database, including 3,870 homozygotes. 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. S28S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (156 hom., cov: 12)
  • Exomes 𝑓: 0.012 (3714 hom.)
• Consequence: KCNE1 NM_000219.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -6.50
• Publications: 6 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, G2P, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-34449551-C-T is Benign according to our data. Variant chr21-34449551-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00652 (527/80802) while in subpopulation AMR AF = 0.0122 (109/8918). AF 95% confidence interval is 0.0104. There are 156 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 12. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 156 AD,AR gene

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.84G>A	p.Ser28Ser	synonymous	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.84G>A	p.Ser28Ser	synonymous	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.84G>A	p.Ser28Ser	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.84G>A	p.Ser28Ser	synonymous	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.84G>A	p.Ser28Ser	synonymous	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.84G>A	p.Ser28Ser	synonymous	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 529 AN: 80758 Hom.: 157 Cov.: 12

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0105

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00238

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.00912

GnomAD2 exomes AF: 0.00362 AC: 909 AN: 251306 AF XY: 0.00355

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.0120 AC: 10604 AN: 886830 Hom.: 3714 Cov.: 21 AF XY: 0.0115 AC XY: 5110 AN XY: 442666

African (AFR) AF: 0.00230 AC: 43 AN: 18706

American (AMR) AF: 0.00847 AC: 278 AN: 32836

Ashkenazi Jewish (ASJ) AF: 0.000126 AC: 2 AN: 15894

East Asian (EAS) AF: 0.000481 AC: 11 AN: 22884

South Asian (SAS) AF: 0.000319 AC: 17 AN: 53214

European-Finnish (FIN) AF: 0.00406 AC: 152 AN: 37442

Middle Eastern (MID) AF: 0.00192 AC: 7 AN: 3646

European-Non Finnish (NFE) AF: 0.0146 AC: 9748 AN: 665448

Other (OTH) AF: 0.00941 AC: 346 AN: 36760

GnomAD4 genome AF: 0.00652 AC: 527 AN: 80802 Hom.: 156 Cov.: 12 AF XY: 0.00591 AC XY: 233 AN XY: 39418

African (AFR) AF: 0.00153 AC: 29 AN: 18912

American (AMR) AF: 0.0122 AC: 109 AN: 8918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1754

East Asian (EAS) AF: 0.00 AC: 0 AN: 2220

South Asian (SAS) AF: 0.00 AC: 0 AN: 2350

European-Finnish (FIN) AF: 0.00238 AC: 16 AN: 6728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 160

European-Non Finnish (NFE) AF: 0.00938 AC: 359 AN: 38276

Other (OTH) AF: 0.00907 AC: 10 AN: 1102

Alfa AF: 0.00483 Hom.: 23

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Jervell and Lange-Nielsen syndrome 2 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 5 (1)
-	-	1	Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.010
DANN	Benign	0.62
PhyloP100		-6.5
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17173510;

hg19: chr21-35821849;