NM_005477.3:c.1210-4081A>G

Variant names:

• chr15-73336373-T-C
• rs2623997
• NM_005477.3:c.1210-4081A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005477.3(HCN4):​c.1210-4081A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,968 control chromosomes in the GnomAD database, including 16,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16313 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101

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]

ENSG00000259650 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1210-4081A>G		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1	n.239+729T>C		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-4081A>G		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1	n.223+729T>C		intron_variant	Intron 2 of 2	2
ENSG00000259650	ENST00000558742.1	n.243+725T>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69849 AN: 151850 Hom.: 16312 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.458

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.460 AC: 69870 AN: 151968 Hom.: 16313 Cov.: 32 AF XY: 0.454 AC XY: 33753 AN XY: 74268

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.495

Gnomad4 EAS AF: 0.532

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.507

Gnomad4 OTH AF: 0.458

Alfa AF: 0.494 Hom.: 17916

Bravo AF: 0.463

Asia WGS AF: 0.421 AC: 1460 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.69

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: rs2623997; hg19: chr15-73628714;