rs79656991

Variant names:

• chr15-73320822-T-C
• rs79656991
• NM_005477.3:c.*1659A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005477.3(HCN4):​c.*1659A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 152,038 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (140 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09
• Publications: 1 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Brugada syndrome 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-73320822-T-C is Benign according to our data. Variant chr15-73320822-T-C is described in ClinVar as Benign. ClinVar VariationId is 886592.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0787 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.*1659A>G		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.*1659A>G		3_prime_UTR	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3616 AN: 151920 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.0212

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 226 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 56

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 130

Other (OTH) AF: 0.00 AC: 0 AN: 30

GnomAD4 genome AF: 0.0238 AC: 3626 AN: 152038 Hom.: 140 Cov.: 32 AF XY: 0.0228 AC XY: 1698 AN XY: 74342

African (AFR) AF: 0.0810 AC: 3359 AN: 41484

American (AMR) AF: 0.00628 AC: 96 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0126 AC: 65 AN: 5152

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67958

Other (OTH) AF: 0.0233 AC: 49 AN: 2100

Alfa AF: 0.0128 Hom.: 13

Bravo AF: 0.0265

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Sick sinus syndrome 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.81
DANN	Benign	0.83
PhyloP100		-1.1
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: rs79656991; hg19: chr15-73613163;