15-73323548-C-T

Position:

• chr15-73323548-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005477.3(HCN4):​c.2545G>A​(p.Val849Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19089153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.2545G>A	p.Val849Met	missense_variant	8/8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.1327G>A	p.Val443Met	missense_variant	7/7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.2545G>A	p.Val849Met	missense_variant	8/8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000424 AC: 1 AN: 235828 Hom.: 0 AF XY: 0.00000778 AC XY: 1 AN XY: 128608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448638 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.13
Sift	Uncertain	0.012	D
Sift4G	Benign	0.21	T
Polyphen		0.38	B
Vest4		0.073
MutPred		0.25		Gain of glycosylation at P852 (P = 0.1061);
MVP		0.67
MPC		0.18
ClinPred		0.28	T
GERP RS		-0.032
Varity_R		0.051
gMVP		0.13

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: rs202138767; hg19: chr15-73615889;