rs56154381

chr5-45267081-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021072.4(HCN1):c.1783+7_1783+8insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,607,762 control chromosomes in the GnomAD database, including 862 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (448 hom., cov: 31)
  • Exomes 𝑓: 0.0098 (414 hom.)
• Consequence: HCN1 NM_021072.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.222

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-45267081-T-TA is Benign according to our data. Variant chr5-45267081-T-TA is described in ClinVar as [Benign]. Clinvar id is 198584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.1783+7_1783+8insT		splice_region_variant, intron_variant		ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.1783+7_1783+8insT		splice_region_variant, intron_variant		1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.1783+7_1783+8insT		splice_region_variant, intron_variant				A2
HCN1	ENST00000637305.1	n.946+7_946+8insT		splice_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6991 AN: 152060 Hom.: 441 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00812

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0162 AC: 4074 AN: 251488 Hom.: 188 AF XY: 0.0136 AC XY: 1854 AN XY: 135918

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00673

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00982 AC: 14299 AN: 1455584 Hom.: 414 Cov.: 28 AF XY: 0.00954 AC XY: 6912 AN XY: 724692

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00889

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00654

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.00624

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0462 AC: 7030 AN: 152178 Hom.: 448 Cov.: 31 AF XY: 0.0452 AC XY: 3365 AN XY: 74414

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00812

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0222 Hom.: 34

Bravo AF: 0.0520

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00984

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs56154381; hg19: chr5-45267183;