15-73335827-T-C

Variant names:

• chr15-73335827-T-C
• rs12905211
• NM_005477.3:c.1210-3535A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B.

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_005477.3(HCN4):​c.1210-3535A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 151,890 control chromosomes in the GnomAD database, including 19,536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19536 hom., cov: 31)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 4 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: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Brugada syndrome 8

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000259650 (HGNC:58475):

LOC105370890 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1210-3535A>G		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1	n.239+183T>C		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-3535A>G		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1	n.223+183T>C		intron_variant	Intron 2 of 2	2
ENSG00000259650	ENST00000558742.1	n.243+179T>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75259 AN: 151772 Hom.: 19523 Cov.: 31

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.512

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.496 AC: 75305 AN: 151890 Hom.: 19536 Cov.: 31 AF XY: 0.499 AC XY: 37052 AN XY: 74226

African (AFR) AF: 0.326 AC: 13521 AN: 41456

American (AMR) AF: 0.559 AC: 8534 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1876 AN: 3466

East Asian (EAS) AF: 0.741 AC: 3791 AN: 5114

South Asian (SAS) AF: 0.501 AC: 2411 AN: 4808

European-Finnish (FIN) AF: 0.590 AC: 6241 AN: 10574

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.548 AC: 37207 AN: 67896

Other (OTH) AF: 0.510 AC: 1072 AN: 2104

Alfa AF: 0.531 Hom.: 34733

Bravo AF: 0.487

Asia WGS AF: 0.571 AC: 1985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs12905211; hg19: chr15-73628168;