NM_005477.3:c.433C>T

Variant names:

• chr15-73367838-G-A
• rs886043525
• NM_005477.3:c.433C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005477.3(HCN4):​c.433C>T​(p.Pro145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,109,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P145L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

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]

HCN4 Gene-Disease associations (from GenCC):

• sick sinus syndrome 2, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Brugada syndrome 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3954363).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005477.3. 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
	HCN4	NM_005477.3	MANE Select	c.433C>T	p.Pro145Ser	missense	Exon 1 of 8	NP_005468.1	Q9Y3Q4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.433C>T	p.Pro145Ser	missense	Exon 1 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000811 AC: 9 AN: 1109528 Hom.: 0 Cov.: 31 AF XY: 0.00000751 AC XY: 4 AN XY: 532626

African (AFR) AF: 0.00 AC: 0 AN: 22586

American (AMR) AF: 0.00 AC: 0 AN: 9612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14360

East Asian (EAS) AF: 0.0000406 AC: 1 AN: 24638

South Asian (SAS) AF: 0.0000671 AC: 2 AN: 29792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2966

European-Non Finnish (NFE) AF: 0.00000533 AC: 5 AN: 938578

Other (OTH) AF: 0.0000227 AC: 1 AN: 44098

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome 8 (1)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.0030
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.36
Sift	Benign	0.068	T
Sift4G	Benign	0.16	T
Polyphen		0.80	P
Vest4		0.11
MutPred		0.26		Gain of phosphorylation at P145 (P = 0.0028)
MVP		0.92
MPC		1.1
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.055
gMVP		0.50
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs886043525; hg19: chr15-73660179;