chr5-45651460-G-A

Variant names:

• chr5-45651460-G-A
• rs4339358
• NM_021072.4:c.426-5852C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021072.4(HCN1):​c.426-5852C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 151,696 control chromosomes in the GnomAD database, including 5,697 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 0.27 (5697 hom., cov: 32)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.426-5852C>T		intron_variant	Intron 1 of 7	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.426-5852C>T		intron_variant	Intron 1 of 7	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.426-5852C>T		intron_variant	Intron 1 of 8			ENSP00000501107.1
HCN1	ENST00000634658.1	c.426-5852C>T		intron_variant	Intron 1 of 1	3		ENSP00000489134.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41161 AN: 151580 Hom.: 5691 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.272 AC: 41195 AN: 151696 Hom.: 5697 Cov.: 32 AF XY: 0.270 AC XY: 19980 AN XY: 74136

African (AFR) AF: 0.272 AC: 11244 AN: 41414

American (AMR) AF: 0.256 AC: 3895 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1084 AN: 3466

East Asian (EAS) AF: 0.323 AC: 1666 AN: 5154

South Asian (SAS) AF: 0.308 AC: 1486 AN: 4818

European-Finnish (FIN) AF: 0.218 AC: 2296 AN: 10544

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18554 AN: 67796

Other (OTH) AF: 0.265 AC: 558 AN: 2108

Alfa AF: 0.173 Hom.: 430

Bravo AF: 0.274

Asia WGS AF: 0.290 AC: 1008 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.097
DANN	Benign	0.24
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs4339358; hg19: chr5-45651562;