21-34449473-G-T

Variant names:

• chr21-34449473-G-T
• NM_000219.6:c.162C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_000219.6(KCNE1):​c.162C>A​(p.Phe54Leu) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F54V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:1
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000219.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449475-A-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.162C>A	p.Phe54Leu	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.162C>A	p.Phe54Leu	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1100726 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 558660

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 16

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Long QT syndrome 5 Other:1

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Roden Lab, Vanderbilt University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	0.055
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D;D;D
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.75	.;.;T;.;.;.;.;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D
Vest4		0.85
MutPred		0.34		Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);
MVP		0.80
MPC		0.44
ClinPred		0.99	D
GERP RS		-6.2
Varity_R		0.59
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-35821771;