rs142735148

Variant names:

• chr15-73322756-T-C
• rs142735148
• NM_005477.3:c.3337A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005477.3(HCN4):​c.3337A>G​(p.Met1113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,562,790 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1113T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 33)
  • Exomes 𝑓: 0.014 (152 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.425
• Publications: 5 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, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Brugada syndrome 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025372803).
• BP6: Variant 15-73322756-T-C is Benign according to our data. Variant chr15-73322756-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0102 (1549/152286) while in subpopulation SAS AF = 0.0207 (100/4826). AF 95% confidence interval is 0.0174. There are 11 homozygotes in GnomAd4. There are 691 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1549 AD gene.

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.3337A>G	p.Met1113Val	missense	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.3337A>G	p.Met1113Val	missense	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1548 AN: 152170 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0116 AC: 1855 AN: 159446 AF XY: 0.0125

Gnomad AFR exome AF: 0.00758

Gnomad AMR exome AF: 0.00807

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0000769

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0136 AC: 19193 AN: 1410504 Hom.: 152 Cov.: 36 AF XY: 0.0140 AC XY: 9740 AN XY: 696756

African (AFR) AF: 0.00727 AC: 238 AN: 32750

American (AMR) AF: 0.00864 AC: 315 AN: 36472

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 378 AN: 25066

East Asian (EAS) AF: 0.0000531 AC: 2 AN: 37646

South Asian (SAS) AF: 0.0234 AC: 1881 AN: 80314

European-Finnish (FIN) AF: 0.00252 AC: 122 AN: 48476

Middle Eastern (MID) AF: 0.0294 AC: 167 AN: 5688

European-Non Finnish (NFE) AF: 0.0140 AC: 15200 AN: 1085518

Other (OTH) AF: 0.0152 AC: 890 AN: 58574

GnomAD4 genome AF: 0.0102 AC: 1549 AN: 152286 Hom.: 11 Cov.: 33 AF XY: 0.00928 AC XY: 691 AN XY: 74448

African (AFR) AF: 0.00645 AC: 268 AN: 41572

American (AMR) AF: 0.00954 AC: 146 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4826

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 895 AN: 68016

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0133 Hom.: 22

Bravo AF: 0.0108

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00669 AC: 29

ESP6500EA AF: 0.0126 AC: 107

ExAC AF: 0.00817 AC: 953

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	1	Brugada syndrome 8 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sick sinus syndrome 2, autosomal dominant (1)
-	-	1	Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.18
DANN	Benign	0.36
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.42
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.18
ClinPred		0.000010	T
GERP RS		-5.1
Varity_R		0.045
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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: rs142735148; hg19: chr15-73615097;