rs56164833

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_021072.4(HCN1):c.124C>T(p.Pro42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,321,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P42P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.84

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 -17 ACMG points.

PP2

Missense variant where missense usually causes diseases, HCN1

BP4

Computational evidence support a benign effect (MetaRNN=0.1733261).

BP6

Variant 5-45695970-G-A is Benign according to our data. Variant chr5-45695970-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 404100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45695970-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000327 (49/149750) while in subpopulation NFE AF= 0.000654 (44/67288). AF 95% confidence interval is 0.0005. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HCN1	ENST00000303230.6 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	1/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	1/9			A2
HCN1	ENST00000634658.1 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000327

AC:

AN:

149750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000654

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000519

AC:

AN:

25072

Hom.:

AF XY:

0.000437

AC XY:

AN XY:

16002

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00104

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.000660

AC:

773

AN:

1171502

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

367

AN XY:

571442

show subpopulations

Gnomad4 AFR exome

AF:

0.0000879

Gnomad4 AMR exome

AF:

0.00

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:

0.000774

Gnomad4 OTH exome

AF:

0.000341

GnomAD4 genome

AF:

0.000327

AC:

AN:

149750

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

AN XY:

73064

show subpopulations

Gnomad4 AFR

AF:

0.0000730

Gnomad4 AMR

AF:

0.0000665

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000102

Gnomad4 NFE

AF:

0.000654

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000359

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HCN1: PP2, PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

-0.00050

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.88

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.86

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.062

T;.

Sift4G

Benign

0.16

T;T

Polyphen

0.079

B;.

Vest4

0.15

MVP

0.60

MPC

2.3

ClinPred

0.043

GERP RS

3.9

Varity_R

0.084

gMVP

0.19

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