15-73321773-T-C

Variant names:

• chr15-73321773-T-C
• rs2623999
• NM_005477.3:c.*708A>G

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.*708A>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 0.83 in 153,422 control chromosomes in the GnomAD database, including 54,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (54167 hom., cov: 32)
  • Exomes 𝑓: 0.91 (536 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.13
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 15-73321773-T-C is Benign according to our data. Variant chr15-73321773-T-C is described in ClinVar as [Benign]. Clinvar id is 884688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.*708A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.*708A>G		3_prime_UTR_variant	Exon 7 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.*708A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.829 AC: 126088 AN: 152012 Hom.: 54155 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.852

GnomAD4 exome AF: 0.913 AC: 1179 AN: 1292 Hom.: 536 Cov.: 0 AF XY: 0.920 AC XY: 675 AN XY: 734

African (AFR) AF: 0.500 AC: 5 AN: 10

American (AMR) AF: 0.922 AC: 59 AN: 64

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.857 AC: 12 AN: 14

South Asian (SAS) AF: 1.00 AC: 10 AN: 10

European-Finnish (FIN) AF: 0.930 AC: 396 AN: 426

Middle Eastern (MID) AF: 1.00 AC: 6 AN: 6

European-Non Finnish (NFE) AF: 0.905 AC: 650 AN: 718

Other (OTH) AF: 0.950 AC: 38 AN: 40

GnomAD4 genome AF: 0.829 AC: 126146 AN: 152130 Hom.: 54167 Cov.: 32 AF XY: 0.833 AC XY: 61948 AN XY: 74376

African (AFR) AF: 0.581 AC: 24088 AN: 41472

American (AMR) AF: 0.921 AC: 14099 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3064 AN: 3468

East Asian (EAS) AF: 0.866 AC: 4444 AN: 5132

South Asian (SAS) AF: 0.830 AC: 3999 AN: 4818

European-Finnish (FIN) AF: 0.939 AC: 9965 AN: 10616

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63595 AN: 68004

Other (OTH) AF: 0.848 AC: 1794 AN: 2116

Alfa AF: 0.879 Hom.: 7036

Bravo AF: 0.819

Asia WGS AF: 0.810 AC: 2816 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sick sinus syndrome 2, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.017
DANN	Benign	0.35
PhyloP100		-3.1
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: rs2623999; hg19: chr15-73614114;