5-45326671-T-G

Variant names:

• chr5-45326671-T-G
• rs1501361
• NM_021072.4:c.1378-22832A>C

Variant summary

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

The NM_021072.4(HCN1):​c.1378-22832A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 151,468 control chromosomes in the GnomAD database, including 10,294 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 0.32 (10294 hom., cov: 33)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.466
• Publications: 2 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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.1378-22832A>C		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.1378-22832A>C		intron	N/A	ENSP00000307342.4
	HCN1	ENST00000673735.1		c.1378-22832A>C		intron	N/A	ENSP00000501107.1
	HCN1	ENST00000637305.1	TSL:5	n.541-22832A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49000 AN: 151350 Hom.: 10254 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.324 AC: 49106 AN: 151468 Hom.: 10294 Cov.: 33 AF XY: 0.326 AC XY: 24131 AN XY: 73984

African (AFR) AF: 0.583 AC: 24120 AN: 41378

American (AMR) AF: 0.316 AC: 4784 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 657 AN: 3460

East Asian (EAS) AF: 0.470 AC: 2396 AN: 5102

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4820

European-Finnish (FIN) AF: 0.189 AC: 1993 AN: 10570

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

European-Non Finnish (NFE) AF: 0.188 AC: 12719 AN: 67708

Other (OTH) AF: 0.284 AC: 595 AN: 2094

Alfa AF: 0.185 Hom.: 811

Bravo AF: 0.346

Asia WGS AF: 0.440 AC: 1526 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.92
DANN	Benign	0.75
PhyloP100		-0.47
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: rs1501361; hg19: chr5-45326773;