rs1555475094

Positions:

• chr15-73322665-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000261917.4(HCN4):​c.3428G>T​(p.Gly1143Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HCN4 ENST00000261917.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

HCN4 (HGNC:16882): (hyperpolarization activated cyclic nucleotide gated potassium channel 4) This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3422166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.3428G>T	p.Gly1143Val	missense_variant	8/8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.2210G>T	p.Gly737Val	missense_variant	7/7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.3428G>T	p.Gly1143Val	missense_variant	8/8	1	NM_005477.3	ENSP00000261917	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2017

In summary, this variant has uncertain impact on HCN4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a HCN4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 1143 of the HCN4 protein (p.Gly1143Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.74	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.069	T
Polyphen		0.42	B
Vest4		0.36
MutPred		0.33		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.90
MPC		0.80
ClinPred		0.39	T
GERP RS		3.3
Varity_R		0.24
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555475094; hg19: chr15-73615006;