Variant chr5-45695893-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021072.4(HCN1):c.201T>C(p.Gly67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,444,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G67G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

HCN1
NM_021072.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 5-45695893-A-G is Benign according to our data. Variant chr5-45695893-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 412770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000219 (30/136974) while in subpopulation AFR AF= 0.000664 (23/34664). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.201T>C	p.Gly67=	synonymous_variant	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HCN1	ENST00000303230.6 linkuse as main transcript	c.201T>C	p.Gly67=	synonymous_variant	1/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1 linkuse as main transcript	c.201T>C	p.Gly67=	synonymous_variant	1/9			A2
HCN1	ENST00000634658.1 linkuse as main transcript	c.201T>C	p.Gly67=	synonymous_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000219

AC:

AN:

136856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000222

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000949

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000142

AC:

AN:

120082

Hom.:

AF XY:

0.000135

AC XY:

AN XY:

66606

show subpopulations

Gnomad AFR exome

AF:

0.000761

Gnomad AMR exome

AF:

0.0000519

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000212

Gnomad SAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.000132

Gnomad NFE exome

AF:

0.000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

134

AN:

1307858

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

645300

show subpopulations

Gnomad4 AFR exome

AF:

0.000722

Gnomad4 AMR exome

AF:

0.0000337

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000231

Gnomad4 SAS exome

AF:

0.0000832

Gnomad4 FIN exome

AF:

0.0000844

Gnomad4 NFE exome

AF:

0.0000857

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000219

AC:

AN:

136974

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

67222

show subpopulations

Gnomad4 AFR

AF:

0.000664

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000223

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000949

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000927

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

HCN1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2020

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

-0.48

CADD

Benign

DANN

Benign

0.55

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

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