chr15-73335429-A-C

Variant names:

• chr15-73335429-A-C
• rs546564
• NM_005477.3:c.1210-3137T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005477.3(HCN4):​c.1210-3137T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,234 control chromosomes in the GnomAD database, including 12,233 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 0.40 (12229 hom., cov: 34)
  • Exomes 𝑓: 0.47 (4 hom.)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 2 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

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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.1210-3137T>G		intron	N/A	NP_005468.1	Q9Y3Q4
	LOC105370890	NR_188273.1		n.74-50A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.1210-3137T>G		intron	N/A	ENSP00000261917.3	Q9Y3Q4
	ENSG00000259650	ENST00000557981.1	TSL:2	n.58-50A>C		intron	N/A
	ENSG00000259650	ENST00000558742.1	TSL:5	n.74-50A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60088 AN: 152086 Hom.: 12201 Cov.: 34

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.0948

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.469 AC: 15 AN: 32 Hom.: 4 Cov.: 0 AF XY: 0.450 AC XY: 9 AN XY: 20

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 10 AN: 20

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.395 AC: 60164 AN: 152202 Hom.: 12229 Cov.: 34 AF XY: 0.390 AC XY: 28997 AN XY: 74412

African (AFR) AF: 0.422 AC: 17517 AN: 41534

American (AMR) AF: 0.430 AC: 6568 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1145 AN: 3468

East Asian (EAS) AF: 0.0952 AC: 493 AN: 5180

South Asian (SAS) AF: 0.336 AC: 1621 AN: 4830

European-Finnish (FIN) AF: 0.309 AC: 3282 AN: 10606

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28233 AN: 67980

Other (OTH) AF: 0.413 AC: 871 AN: 2110

Alfa AF: 0.377 Hom.: 3798

Bravo AF: 0.404

Asia WGS AF: 0.250 AC: 873 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		0.12
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: rs546564; hg19: chr15-73627770;