rs1165134160

Variant names:

• chr15-73322740-A-G
• rs1165134160
• NM_005477.3:c.3353T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-73322740-A-G
• chr15-73322740-A-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005477.3(HCN4):​c.3353T>C​(p.Leu1118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,562,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. L1118H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.383
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07628617).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000092 (14/152218) while in subpopulation AMR AF = 0.000916 (14/15284). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 14 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.3353T>C	p.Leu1118Pro	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.3353T>C	p.Leu1118Pro	missense	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000440 AC: 7 AN: 158930 AF XY: 0.0000350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000277

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000496 AC: 7 AN: 1410648 Hom.: 0 Cov.: 36 AF XY: 0.00000430 AC XY: 3 AN XY: 696872

African (AFR) AF: 0.00 AC: 0 AN: 32654

American (AMR) AF: 0.000192 AC: 7 AN: 36524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 37348

South Asian (SAS) AF: 0.00 AC: 0 AN: 80438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085760

Other (OTH) AF: 0.00 AC: 0 AN: 58552

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000916 AC: 14 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.38
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.18		Gain of glycosylation at L1118 (P = 0.0449)
MVP		0.47
MPC		0.32
ClinPred		0.024	T
GERP RS		-0.52
Varity_R		0.10
gMVP		0.18
Mutation Taster		=82/18	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: rs1165134160; hg19: chr15-73615081;