rs764493888

Variant names:

• chr15-73325310-C-G
• rs764493888
• NM_005477.3:c.1725G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-73325310-C-G
• chr15-73325310-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005477.3(HCN4):​c.1725G>C​(p.Glu575Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E575K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.35
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30652106).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.1725G>C	p.Glu575Asp	missense	Exon 5 of 8	NP_005468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.1725G>C	p.Glu575Asp	missense	Exon 5 of 8	ENSP00000261917.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000780 AC: 16 AN: 205012 AF XY: 0.0000731

Gnomad AFR exome AF: 0.0000731

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000929

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000632

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000190

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000982 AC: 14 AN: 1426132 Hom.: 0 Cov.: 33 AF XY: 0.0000113 AC XY: 8 AN XY: 705874

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32846

American (AMR) AF: 0.00 AC: 0 AN: 39954

Ashkenazi Jewish (ASJ) AF: 0.000251 AC: 6 AN: 23916

East Asian (EAS) AF: 0.00 AC: 0 AN: 38136

South Asian (SAS) AF: 0.00 AC: 0 AN: 78522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1100034

Other (OTH) AF: 0.00 AC: 0 AN: 59154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000445 Hom.: 0

ExAC AF: 0.000321 AC: 39

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	-0.35	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.45
Sift	Benign	0.22	T
Sift4G	Benign	0.27	T
Polyphen		0.89	P
Vest4		0.55
MutPred		0.36		Gain of helix (P = 0.0854)
MVP		0.91
MPC		1.0
ClinPred		0.071	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.46
Mutation Taster		=33/67	disease causing

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: rs764493888; hg19: chr15-73617651;