rs376434225

Positions:

chr5-45267256-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021072.4(HCN1):c.1619-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

HCN1
NM_021072.4 splice_region, intron

Scores

Splicing: ADA: 0.00004036

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.43

Variant links:

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 links:

HCN1 (HGNC:):

HCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-45267256-A-G is Benign according to our data. Variant chr5-45267256-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 502430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr5-45267256-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000585 (89/152228) while in subpopulation AFR AF= 0.00197 (82/41546). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.1619-3T>C		splice_region_variant, intron_variant		ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
HCN1	ENST00000303230.6 linkuse as main transcript	c.1619-3T>C	splice_region_variant, intron_variant	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 linkuse as main transcript	c.1619-3T>C	splice_region_variant, intron_variant			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000637305.1 linkuse as main transcript	n.782-3T>C	splice_region_variant, intron_variant	5

Frequencies

GnomAD3 genomes

AF:

0.000579

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251300

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000585

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000646

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

HCN1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.0

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.026

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over