rs372398235

Variant names:

• chr21-34449529-G-A
• rs372398235
• NM_000219.6:c.106C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34449529-G-A
• chr21-34449529-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000219.6(KCNE1):​c.106C>T​(p.Arg36Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000050 (2 hom., cov: 11)
  • Exomes 𝑓: 0.0000083 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -2.44
• Publications: 3 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24819806).
• BP6: Variant 21-34449529-G-A is Benign according to our data. Variant chr21-34449529-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 518804.
• BS2: High Homozygotes in GnomAd4 at 2 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.106C>T	p.Arg36Cys	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.106C>T	p.Arg36Cys	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.106C>T	p.Arg36Cys	missense	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.106C>T	p.Arg36Cys	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.106C>T	p.Arg36Cys	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.106C>T	p.Arg36Cys	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.0000496 AC: 4 AN: 80572 Hom.: 2 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000225

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: 0.0000522

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251368 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000827 AC: 7 AN: 845936 Hom.: 3 Cov.: 23 AF XY: 0.00000238 AC XY: 1 AN XY: 420738

African (AFR) AF: 0.00 AC: 0 AN: 16396

American (AMR) AF: 0.0000698 AC: 2 AN: 28652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13804

East Asian (EAS) AF: 0.00 AC: 0 AN: 18416

South Asian (SAS) AF: 0.00 AC: 0 AN: 48928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3426

European-Non Finnish (NFE) AF: 0.00000773 AC: 5 AN: 646458

Other (OTH) AF: 0.00 AC: 0 AN: 34372

GnomAD4 genome AF: 0.0000496 AC: 4 AN: 80572 Hom.: 2 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 39312

African (AFR) AF: 0.00 AC: 0 AN: 18728

American (AMR) AF: 0.000225 AC: 2 AN: 8886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1730

East Asian (EAS) AF: 0.00 AC: 0 AN: 2216

South Asian (SAS) AF: 0.00 AC: 0 AN: 2332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.0000522 AC: 2 AN: 38290

Other (OTH) AF: 0.00 AC: 0 AN: 1106

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.50
Sift	Benign	0.054	T
Sift4G	Benign	0.064	T
Polyphen		0.85	P
Vest4		0.12
MVP		0.79
MPC		0.31
ClinPred		0.11	T
GERP RS		-5.1
Varity_R		0.055
gMVP		0.50
Mutation Taster		=90/10	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: rs372398235; hg19: chr21-35821827; COSMIC: COSV100492419;