chr21-34449526-T-C

Variant names:

• chr21-34449526-T-C
• rs202036483
• NM_000219.6:c.109A>G

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S37R) 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
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• 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=0.0904592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.109A>G	p.Ser37Gly	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.109A>G	p.Ser37Gly	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251384 AF XY: 0.0000147

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: 0.00000880

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

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

American (AMR) AF: 0.00 AC: 0 AN: 28664

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 18398

South Asian (SAS) AF: 0.0000409 AC: 2 AN: 48958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35572

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

European-Non Finnish (NFE) AF: 0.000105 AC: 68 AN: 647236

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

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

Aug 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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
LIST_S2	Benign	0.33	.;.;T;.;.;.;.;.
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
PhyloP100		-1.2
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		0.030
gMVP		0.45
Mutation Taster		=60/40	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: rs202036483; hg19: chr21-35821824;