NM_005477.3:c.*1989G>A

Variant names:

• chr15-73320492-C-T
• rs549377
• NM_005477.3:c.*1989G>A

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.*1989G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,198 control chromosomes in the GnomAD database, including 52,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (51998 hom., cov: 31)
  • Exomes 𝑓: 0.87 (24 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.40
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 15-73320492-C-T is Benign according to our data. Variant chr15-73320492-C-T is described in ClinVar as Benign. ClinVar VariationId is 886590.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.*1989G>A		3_prime_UTR	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.*1989G>A		3_prime_UTR	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122685 AN: 152018 Hom.: 51986 Cov.: 31

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.832

GnomAD4 exome AF: 0.871 AC: 54 AN: 62 Hom.: 24 Cov.: 0 AF XY: 0.854 AC XY: 41 AN XY: 48

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.957 AC: 44 AN: 46

Other (OTH) AF: 0.833 AC: 5 AN: 6

GnomAD4 genome AF: 0.807 AC: 122733 AN: 152136 Hom.: 51998 Cov.: 31 AF XY: 0.810 AC XY: 60278 AN XY: 74392

African (AFR) AF: 0.519 AC: 21529 AN: 41448

American (AMR) AF: 0.911 AC: 13924 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3050 AN: 3472

East Asian (EAS) AF: 0.813 AC: 4205 AN: 5170

South Asian (SAS) AF: 0.822 AC: 3967 AN: 4826

European-Finnish (FIN) AF: 0.928 AC: 9840 AN: 10608

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63374 AN: 68002

Other (OTH) AF: 0.827 AC: 1748 AN: 2114

Alfa AF: 0.895 Hom.: 53332

Bravo AF: 0.795

Asia WGS AF: 0.767 AC: 2666 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.98
CADD	Benign	0.12
DANN	Benign	0.45
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs549377; hg19: chr15-73612833;