21-34449612-G-T

Variant names:

• chr21-34449612-G-T
• rs199473348
• NM_000219.6:c.23C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000219.6(KCNE1):​c.23C>A​(p.Ala8Glu) variant causes a missense 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 14 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12973332).

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.23C>A	p.Ala8Glu	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.23C>A	p.Ala8Glu	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.23C>A	p.Ala8Glu	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.23C>A	p.Ala8Glu	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.23C>A	p.Ala8Glu	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.23C>A	p.Ala8Glu	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251178 AF XY: 0.00000736

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 795712 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 409652

African (AFR) AF: 0.00 AC: 0 AN: 19648

American (AMR) AF: 0.00 AC: 0 AN: 36682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19120

East Asian (EAS) AF: 0.00 AC: 0 AN: 33344

South Asian (SAS) AF: 0.00 AC: 0 AN: 63976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3814

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 539172

Other (OTH) AF: 0.00 AC: 0 AN: 37712

GnomAD4 genome Cov.: 13

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	6.2
DANN	Benign	0.44
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.56
Sift	Benign	0.095	T
Sift4G	Benign	0.91	T
Polyphen		0.0030	B
Vest4		0.14
MutPred		0.42		Gain of solvent accessibility (P = 0.005)
MVP		0.74
MPC		0.12
ClinPred		0.058	T
GERP RS		0.94
Varity_R		0.061
gMVP		0.57
Mutation Taster		=25/75	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: rs199473348; hg19: chr21-35821910;