rs117731813

Variant names:

• chr15-73325094-G-A
• rs117731813
• NM_005477.3:c.1839C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-73325094-G-A
• chr15-73325094-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005477.3(HCN4):​c.1839C>T​(p.Phe613Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,614,214 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (256 hom.)
• Consequence: HCN4 NM_005477.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.83
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-73325094-G-A is Benign according to our data. Variant chr15-73325094-G-A is described in ClinVar as Benign. ClinVar VariationId is 137541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0732 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.1839C>T	p.Phe613Phe	synonymous	Exon 6 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.1839C>T	p.Phe613Phe	synonymous	Exon 6 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1703 AN: 152204 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0795

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0181 AC: 4560 AN: 251496 AF XY: 0.0154

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0732

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00563 AC: 8226 AN: 1461892 Hom.: 256 Cov.: 33 AF XY: 0.00526 AC XY: 3824 AN XY: 727246

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.0669 AC: 2990 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0670 AC: 2658 AN: 39700

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86256

European-Finnish (FIN) AF: 0.0267 AC: 1427 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000260 AC: 289 AN: 1112012

Other (OTH) AF: 0.00955 AC: 577 AN: 60396

GnomAD4 genome AF: 0.0112 AC: 1702 AN: 152322 Hom.: 63 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74478

African (AFR) AF: 0.00142 AC: 59 AN: 41584

American (AMR) AF: 0.0524 AC: 801 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0795 AC: 411 AN: 5168

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0307 AC: 326 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.00429 Hom.: 11

Bravo AF: 0.0126

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Brugada syndrome 8 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Sick sinus syndrome 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.78
PhyloP100		-1.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs117731813; hg19: chr15-73617435; COSMIC: COSV56081848;