rs481579

Variant names:

• chr15-73324294-T-C
• rs481579
• NM_005477.3:c.1979-41A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-73324294-T-C
• chr15-73324294-T-A
• chr15-73324294-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005477.3(HCN4):​c.1979-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,607,054 control chromosomes in the GnomAD database, including 664,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (52669 hom., cov: 34)
  • Exomes 𝑓: 0.91 (611679 hom.)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0590
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-73324294-T-C is Benign according to our data. Variant chr15-73324294-T-C is described in ClinVar as Benign. ClinVar VariationId is 259779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.926 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.1979-41A>G		intron	N/A	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.1979-41A>G		intron	N/A	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123857 AN: 152108 Hom.: 52656 Cov.: 34

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.879

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.838

GnomAD2 exomes AF: 0.885 AC: 210391 AN: 237842 AF XY: 0.888

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.948

Gnomad ASJ exome AF: 0.873

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.926

Gnomad NFE exome AF: 0.929

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.914 AC: 1330440 AN: 1454828 Hom.: 611679 Cov.: 37 AF XY: 0.913 AC XY: 660167 AN XY: 723454

African (AFR) AF: 0.530 AC: 17662 AN: 33316

American (AMR) AF: 0.943 AC: 41248 AN: 43738

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 22770 AN: 26006

East Asian (EAS) AF: 0.838 AC: 33037 AN: 39408

South Asian (SAS) AF: 0.834 AC: 71489 AN: 85678

European-Finnish (FIN) AF: 0.928 AC: 48407 AN: 52174

Middle Eastern (MID) AF: 0.855 AC: 4713 AN: 5512

European-Non Finnish (NFE) AF: 0.936 AC: 1037685 AN: 1108896

Other (OTH) AF: 0.889 AC: 53429 AN: 60100

GnomAD4 genome AF: 0.814 AC: 123907 AN: 152226 Hom.: 52669 Cov.: 34 AF XY: 0.817 AC XY: 60848 AN XY: 74438

African (AFR) AF: 0.543 AC: 22537 AN: 41508

American (AMR) AF: 0.913 AC: 13966 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 3051 AN: 3472

East Asian (EAS) AF: 0.817 AC: 4212 AN: 5154

South Asian (SAS) AF: 0.829 AC: 4001 AN: 4826

European-Finnish (FIN) AF: 0.928 AC: 9861 AN: 10630

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63424 AN: 68018

Other (OTH) AF: 0.833 AC: 1757 AN: 2110

Alfa AF: 0.885 Hom.: 15721

Bravo AF: 0.803

Asia WGS AF: 0.775 AC: 2697 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.55
DANN	Benign	0.35
PhyloP100		-0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs481579; hg19: chr15-73616635; COSMIC: COSV56083853;