NM_000219.6:c.32C>G

Variant names:

• chr21-34449603-G-C
• rs771981567
• NM_000219.6:c.32C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000219.6(KCNE1):​c.32C>G​(p.Pro11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. P11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000024 (0 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: 2.09
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

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.32C>G	p.Pro11Arg	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.32C>G	p.Pro11Arg	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.32C>G	p.Pro11Arg	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.32C>G	p.Pro11Arg	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.32C>G	p.Pro11Arg	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.32C>G	p.Pro11Arg	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251280 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000245 AC: 2 AN: 817696 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 419044

African (AFR) AF: 0.00 AC: 0 AN: 19688

American (AMR) AF: 0.0000543 AC: 2 AN: 36828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18794

East Asian (EAS) AF: 0.00 AC: 0 AN: 31398

South Asian (SAS) AF: 0.00 AC: 0 AN: 63688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 564016

Other (OTH) AF: 0.00 AC: 0 AN: 37880

GnomAD4 genome Cov.: 13

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.061
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.56
Sift	Benign	0.20	T
Sift4G	Benign	0.087	T
Polyphen		0.87	P
Vest4		0.33
MutPred		0.44		Gain of MoRF binding (P = 1e-04)
MVP		0.93
MPC		0.19
ClinPred		0.50	T
GERP RS		3.9
Varity_R		0.084
gMVP		0.56
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs771981567; hg19: chr21-35821901;