rs202036483

chr21-34449526-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000219.6(KCNE1):c.109A>G(p.Ser37Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S37N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.000083 (28 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0904592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.109A>G	p.Ser37Gly	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.109A>G	p.Ser37Gly	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251384 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135890

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000827 AC: 70 AN: 846826 Hom.: 28 Cov.: 23 AF XY: 0.0000831 AC XY: 35 AN XY: 421108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000409

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

Alfa AF: 0.0000902 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.012
Dann	Benign	0.55
DEOGEN2	Uncertain	0.58	D;D;D;D;D;D;D;D
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0080	N
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.090	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-0.81	N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.40	T;.;.;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;B
Vest4		0.029
MutPred		0.14		Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);Loss of phosphorylation at S37 (P = 0.0231);
MVP		0.42
MPC		0.069
ClinPred		0.048	T
GERP RS		-9.9
Varity_R		0.032
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs202036483; hg19: chr21-35821824;