rs1604320

Variant names:

• chr5-45307491-G-A
• rs1604320
• NM_021072.4:c.1378-3652C>T

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.1378-3652C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 152,192 control chromosomes in the GnomAD database, including 92 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 (92 hom., cov: 32)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160
• 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=-0.98).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0296 (4499/152192) while in subpopulation NFE AF = 0.0407 (2767/68004). AF 95% confidence interval is 0.0394. There are 92 homozygotes in GnomAd4. There are 2215 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.1378-3652C>T		intron_variant	Intron 5 of 7	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.1378-3652C>T		intron_variant	Intron 5 of 7	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.1378-3652C>T		intron_variant	Intron 5 of 8			ENSP00000501107.1
HCN1	ENST00000637305.1	n.541-3652C>T		intron_variant	Intron 4 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4502 AN: 152074 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.0485

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0310

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

GnomAD4 genome AF: 0.0296 AC: 4499 AN: 152192 Hom.: 92 Cov.: 32 AF XY: 0.0298 AC XY: 2215 AN XY: 74404

African (AFR) AF: 0.00753 AC: 313 AN: 41558

American (AMR) AF: 0.0287 AC: 438 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4832

European-Finnish (FIN) AF: 0.0530 AC: 561 AN: 10592

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0407 AC: 2767 AN: 68004

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0333 Hom.: 24

Bravo AF: 0.0275

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.69
DANN	Benign	0.35
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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: rs1604320; hg19: chr5-45307593;