15-73320127-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005477.3(HCN4):c.*2354A>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 0.0132 in 152,570 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (0 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0180

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-73320127-T-C is Benign according to our data. Variant chr15-73320127-T-C is described in ClinVar as [Benign]. Clinvar id is 885568.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2007/152262) while in subpopulation NFE AF= 0.0213 (1450/67998). AF 95% confidence interval is 0.0204. There are 25 homozygotes in gnomad4. There are 909 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2009 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*2354A>G		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*2354A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*2354A>G		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2009 AN: 152144 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00649 AC: 2 AN: 308 Hom.: 0 Cov.: 0 AF XY: 0.00397 AC XY: 1 AN XY: 252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00781

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0132 AC: 2007 AN: 152262 Hom.: 25 Cov.: 32 AF XY: 0.0122 AC XY: 909 AN XY: 74474

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0139

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0170 Hom.: 7

Bravo AF: 0.0129

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sick sinus syndrome 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.76
Dann	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs11631286; hg19: chr15-73612468; COSMIC: COSV56085789;