NM_172201.2:c.13T>C

Variant names:

• chr21-34370491-T-C
• rs2123423458
• NM_172201.2:c.13T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172201.2(KCNE2):​c.13T>C​(p.Ser5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. S5F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

Genes affected

KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

KCNE2 Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000225555 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116451144).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172201.2. 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
	KCNE2	NM_172201.2	MANE Select	c.13T>C	p.Ser5Pro	missense	Exon 2 of 2	NP_751951.1	Q9Y6J6
	LOC105372791	NR_188571.1		n.796A>G		non_coding_transcript_exon	Exon 2 of 3
	LOC105372791	NR_188572.1		n.796A>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE2	ENST00000290310.4	TSL:1 MANE Select	c.13T>C	p.Ser5Pro	missense	Exon 2 of 2	ENSP00000290310.2	Q9Y6J6
	KCNE2	ENST00000715813.1		c.13T>C	p.Ser5Pro	missense	Exon 6 of 6	ENSP00000520524.1	Q9Y6J6
	ENSG00000225555	ENST00000440403.2	TSL:3	n.798A>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Atrial fibrillation, familial, 4;C3150953:Long QT syndrome 6 (1)
-	1	-	Long QT syndrome 6 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.22
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.10
Sift	Benign	0.039	D
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.078
MutPred		0.21		Loss of helix (P = 0.0167)
MVP		0.65
MPC		0.14
ClinPred		0.048	T
GERP RS		-1.8
Varity_R		0.17
gMVP		0.94
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2123423458; hg19: chr21-35742790;