chr15-73321284-A-G

Position:

• chr15-73321284-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005477.3(HCN4):​c.*1197T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 152,254 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (117 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.272

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=-0.87).
• BP6: Variant 15-73321284-A-G is Benign according to our data. Variant chr15-73321284-A-G is described in ClinVar as [Benign]. Clinvar id is 887841.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest population allele frequency = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*1197T>C		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*1197T>C		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*1197T>C		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4514 AN: 152126 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0809

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.0297 AC: 4516 AN: 152244 Hom.: 117 Cov.: 32 AF XY: 0.0309 AC XY: 2303 AN XY: 74440

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0809

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0366 Hom.: 27

Bravo AF: 0.0232

Asia WGS AF: 0.00751 AC: 26 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	-0.87
CADD	Benign	3.3
DANN	Benign	0.76

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: rs117071871; hg19: chr15-73613625;