rs13163424

Variant names:

• chr5-45419486-C-T
• rs13163424
• NM_021072.4:c.1012-22776G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_021072.4(HCN1):​c.1012-22776G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 152,272 control chromosomes in the GnomAD database, including 103 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 0.030 (103 hom., cov: 31)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 1 publications found

Genes affected

HCN1 (HGNC:4845): (hyperpolarization activated cyclic nucleotide gated potassium channel 1) The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

HCN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• generalized epilepsy with febrile seizures plus, type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0303 (4612/152272) while in subpopulation NFE AF = 0.045 (3062/68022). AF 95% confidence interval is 0.0437. There are 103 homozygotes in GnomAd4. There are 2126 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4612 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.1012-22776G>A		intron_variant	Intron 3 of 7	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.1012-22776G>A		intron_variant	Intron 3 of 7	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.1012-22776G>A		intron_variant	Intron 3 of 8			ENSP00000501107.1
HCN1	ENST00000637305.1	n.175-22776G>A		intron_variant	Intron 2 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4610 AN: 152154 Hom.: 103 Cov.: 31

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0320

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

GnomAD4 genome AF: 0.0303 AC: 4612 AN: 152272 Hom.: 103 Cov.: 31 AF XY: 0.0286 AC XY: 2126 AN XY: 74450

African (AFR) AF: 0.0103 AC: 427 AN: 41564

American (AMR) AF: 0.0290 AC: 444 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4824

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3062 AN: 68022

Other (OTH) AF: 0.0321 AC: 68 AN: 2116

Alfa AF: 0.0348 Hom.: 79

Bravo AF: 0.0305

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs13163424; hg19: chr5-45419588;