5-45285616-A-C

Variant names:

• chr5-45285616-A-C
• rs981782
• NM_021072.4:c.1618+17983T>G

Variant summary

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

The NM_021072.4(HCN1):​c.1618+17983T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 151,870 control chromosomes in the GnomAD database, including 11,283 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 0.34 (11283 hom., cov: 32)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.654
• Publications: 61 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=-0.56).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.1618+17983T>G		intron	N/A	NP_066550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.1618+17983T>G		intron	N/A	ENSP00000307342.4
	HCN1	ENST00000673735.1		c.1618+17983T>G		intron	N/A	ENSP00000501107.1
	HCN1	ENST00000637305.1	TSL:5	n.781+17983T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52268 AN: 151752 Hom.: 11285 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.384

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

GnomAD4 genome AF: 0.344 AC: 52266 AN: 151870 Hom.: 11283 Cov.: 32 AF XY: 0.344 AC XY: 25540 AN XY: 74172

African (AFR) AF: 0.0842 AC: 3497 AN: 41518

American (AMR) AF: 0.415 AC: 6301 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1395 AN: 3462

East Asian (EAS) AF: 0.324 AC: 1668 AN: 5154

South Asian (SAS) AF: 0.199 AC: 961 AN: 4826

European-Finnish (FIN) AF: 0.553 AC: 5840 AN: 10554

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31180 AN: 67856

Other (OTH) AF: 0.382 AC: 806 AN: 2110

Alfa AF: 0.416 Hom.: 27012

Bravo AF: 0.328

Asia WGS AF: 0.256 AC: 894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.65
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: rs981782; hg19: chr5-45285718; COSMIC: COSV57495154;