15-73323538-G-T

Variant names:

• chr15-73323538-G-T
• rs779241036
• NM_005477.3:c.2555C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005477.3(HCN4):​c.2555C>A​(p.Pro852Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P852P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.2555C>A	p.Pro852Gln	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.1337C>A	p.Pro446Gln	missense_variant	Exon 7 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.2555C>A	p.Pro852Gln	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.0043	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.24		Gain of solvent accessibility (P = 0.0137);
MVP		0.91
MPC		0.16
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.18
gMVP		0.39

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: rs779241036; hg19: chr15-73615879;