15-73322493-T-C

Variant names:

• chr15-73322493-T-C
• rs529004
• NM_005477.3:c.3600A>G

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.3600A>G​(p.Pro1200Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,593,540 control chromosomes in the GnomAD database, including 678,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1200P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.88 (59827 hom., cov: 33)
  • Exomes 𝑓: 0.93 (618688 hom.)
• Consequence: HCN4 NM_005477.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.66
• Publications: 23 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 15-73322493-T-C is Benign according to our data. Variant chr15-73322493-T-C is described in ClinVar as Benign. ClinVar VariationId is 95285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.93 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.3600A>G	p.Pro1200Pro	synonymous	Exon 8 of 8	NP_005468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.3600A>G	p.Pro1200Pro	synonymous	Exon 8 of 8	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134341 AN: 152096 Hom.: 59793 Cov.: 33

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.899

GnomAD2 exomes AF: 0.907 AC: 196449 AN: 216572 AF XY: 0.906

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.960

Gnomad ASJ exome AF: 0.879

Gnomad EAS exome AF: 0.882

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.932

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.926 AC: 1334281 AN: 1441326 Hom.: 618688 Cov.: 42 AF XY: 0.923 AC XY: 660210 AN XY: 715248

African (AFR) AF: 0.753 AC: 24885 AN: 33040

American (AMR) AF: 0.958 AC: 40310 AN: 42090

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 22653 AN: 25706

East Asian (EAS) AF: 0.895 AC: 34737 AN: 38802

South Asian (SAS) AF: 0.841 AC: 69972 AN: 83244

European-Finnish (FIN) AF: 0.934 AC: 48045 AN: 51430

Middle Eastern (MID) AF: 0.892 AC: 5108 AN: 5726

European-Non Finnish (NFE) AF: 0.939 AC: 1034155 AN: 1101690

Other (OTH) AF: 0.913 AC: 54416 AN: 59598

GnomAD4 genome AF: 0.883 AC: 134432 AN: 152214 Hom.: 59827 Cov.: 33 AF XY: 0.885 AC XY: 65848 AN XY: 74434

African (AFR) AF: 0.765 AC: 31737 AN: 41508

American (AMR) AF: 0.941 AC: 14403 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3067 AN: 3468

East Asian (EAS) AF: 0.880 AC: 4538 AN: 5156

South Asian (SAS) AF: 0.841 AC: 4058 AN: 4826

European-Finnish (FIN) AF: 0.937 AC: 9947 AN: 10616

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63682 AN: 68014

Other (OTH) AF: 0.896 AC: 1893 AN: 2112

Alfa AF: 0.911 Hom.: 42321

Bravo AF: 0.880

Asia WGS AF: 0.838 AC: 2915 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	not provided (2)
-	-	1	Brugada syndrome 8 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sick sinus syndrome 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.7
DANN	Benign	0.63
PhyloP100		-1.7
Mutation Taster		=99/1	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: rs529004; hg19: chr15-73614834; COSMIC: COSV56082155;