NM_000219.6:c.-162+3327C>A

Variant names:

• chr21-34507774-G-T
• rs727957
• NM_000219.6:c.-162+3327C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000219.6(KCNE1):​c.-162+3327C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,194 control chromosomes in the GnomAD database, including 1,663 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1663 hom., cov: 32)
• Consequence: KCNE1 NM_000219.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 33 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.-162+3327C>A		intron_variant	Intron 2 of 3	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.-162+3327C>A		intron_variant	Intron 2 of 3	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19824 AN: 152076 Hom.: 1663 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.131

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.130 AC: 19822 AN: 152194 Hom.: 1663 Cov.: 32 AF XY: 0.131 AC XY: 9762 AN XY: 74394

African (AFR) AF: 0.0372 AC: 1546 AN: 41558

American (AMR) AF: 0.122 AC: 1860 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3466

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5184

South Asian (SAS) AF: 0.183 AC: 881 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10566

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12605 AN: 67992

Other (OTH) AF: 0.129 AC: 273 AN: 2112

Alfa AF: 0.160 Hom.: 9853

Bravo AF: 0.118

Asia WGS AF: 0.0870 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.81
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs727957; hg19: chr21-35880072;