rs148453034

Variant names:

• chr15-73332146-G-A
• rs148453034
• NM_005477.3:c.1356C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005477.3(HCN4):​c.1356C>T​(p.Ser452Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00171 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: HCN4 NM_005477.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 4.05
• 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 15-73332146-G-A is Benign according to our data. Variant chr15-73332146-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286612.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (168/152338) while in subpopulation NFE AF = 0.00165 (112/68038). AF 95% confidence interval is 0.0014. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 168 AD gene.

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.1356C>T	p.Ser452Ser	synonymous	Exon 3 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.1356C>T	p.Ser452Ser	synonymous	Exon 3 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000998 AC: 251 AN: 251446 AF XY: 0.00101

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00177 AC: 2585 AN: 1461708 Hom.: 5 Cov.: 32 AF XY: 0.00175 AC XY: 1275 AN XY: 727140

African (AFR) AF: 0.000179 AC: 6 AN: 33472

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00218 AC: 2419 AN: 1111980

Other (OTH) AF: 0.00123 AC: 74 AN: 60374

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74482

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.00144 AC: 22 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00102

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	3	not provided (4)
-	-	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	-0.32
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		4.0
Mutation Taster		=100/0	polymorphism

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: rs148453034; hg19: chr15-73624487;