15-73323537-C-T

Variant names:

• chr15-73323537-C-T
• rs117819825
• NM_005477.3:c.2556G>A

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.2556G>A​(p.Pro852Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,601,002 control chromosomes in the GnomAD database, including 1,989 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. P852P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.037 (150 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1839 hom.)
• Consequence: HCN4 NM_005477.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.21
• Publications: 10 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=-0.73).
• BP6: Variant 15-73323537-C-T is Benign according to our data. Variant chr15-73323537-C-T is described in ClinVar as Benign. ClinVar VariationId is 95284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0726 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.2556G>A	p.Pro852Pro	synonymous	Exon 8 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.2556G>A	p.Pro852Pro	synonymous	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5651 AN: 152160 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0758

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0493

GnomAD2 exomes AF: 0.0489 AC: 11512 AN: 235532 AF XY: 0.0476

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0501

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0461 AC: 66785 AN: 1448724 Hom.: 1839 Cov.: 36 AF XY: 0.0460 AC XY: 33153 AN XY: 721108

African (AFR) AF: 0.00839 AC: 281 AN: 33474

American (AMR) AF: 0.105 AC: 4692 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 575 AN: 26124

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39692

South Asian (SAS) AF: 0.0471 AC: 4066 AN: 86256

European-Finnish (FIN) AF: 0.0236 AC: 958 AN: 40590

Middle Eastern (MID) AF: 0.0406 AC: 234 AN: 5764

European-Non Finnish (NFE) AF: 0.0481 AC: 53430 AN: 1111816

Other (OTH) AF: 0.0421 AC: 2539 AN: 60300

GnomAD4 genome AF: 0.0372 AC: 5661 AN: 152278 Hom.: 150 Cov.: 33 AF XY: 0.0366 AC XY: 2727 AN XY: 74456

African (AFR) AF: 0.0112 AC: 465 AN: 41544

American (AMR) AF: 0.0763 AC: 1167 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0468 AC: 226 AN: 4834

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3409 AN: 68010

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.0196 Hom.: 15

Bravo AF: 0.0402

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0518

EpiControl AF: 0.0529

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.73
CADD	Benign	1.4
DANN	Benign	0.60
PhyloP100		-4.2
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: rs117819825; hg19: chr15-73615878; COSMIC: COSV56082975;