rs150454912

Variant names:

• chr21-34449342-C-G
• rs150454912
• NM_000219.6:c.293G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-34449342-C-G
• chr21-34449342-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_000219.6(KCNE1):​c.293G>C​(p.Arg98Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• Publications: 9 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: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449343-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132676.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

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.293G>C	p.Arg98Pro	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.293G>C	p.Arg98Pro	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.293G>C	p.Arg98Pro	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.293G>C	p.Arg98Pro	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1443082 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 718902

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094556

Other (OTH) AF: 0.00 AC: 0 AN: 59806

GnomAD4 genome Cov.: 17

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	KCNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.51		Loss of helix (P = 0.0104)
MVP		0.92
MPC		0.51
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.88
Mutation Taster		=38/62	disease causing

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: rs150454912; hg19: chr21-35821640;