21-34449343-G-C

Variant names:

• chr21-34449343-G-C
• rs199473362
• NM_000219.6:c.292C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000219.6(KCNE1):​c.292C>G​(p.Arg98Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.58
• Publications: 22 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.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.292C>G	p.Arg98Gly	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.292C>G	p.Arg98Gly	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.292C>G	p.Arg98Gly	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.292C>G	p.Arg98Gly	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.292C>G	p.Arg98Gly	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.292C>G	p.Arg98Gly	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.41
MutPred		0.48		Loss of stability (P = 0.0247)
MVP		0.93
MPC		0.48
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.73
Mutation Taster		=21/79	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: rs199473362; hg19: chr21-35821641;