Genetic Variant HCN1:p.Pro879Ser (chr5-45261959-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_021072.4(HCN1):c.2635C>T(p.Pro879Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.11

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in the HCN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 59 curated benign missense variants. Gene score misZ: 3.6647 (above the threshold of 3.09). Trascript score misZ: 3.2427 (above the threshold of 3.09). GenCC associations: The gene is linked to generalized epilepsy with febrile seizures plus, type 10, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 24, generalized epilepsy with febrile seizures plus.

BP4

Computational evidence support a benign effect (MetaRNN=0.026440263).

BP6

Variant 5-45261959-G-A is Benign according to our data. Variant chr5-45261959-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1554103.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.2635C>T	p.Pro879Ser	missense_variant	Exon 8 of 8	ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCN1	ENST00000303230.6 link	c.2635C>T	p.Pro879Ser	missense_variant	Exon 8 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735 link	c.*860C>T		3_prime_UTR_variant	Exon 9 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000637305.1 link	n.1798C>T		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250940

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

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:

0.00000752

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

May 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.11

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.63

M_CAP

Benign

0.018

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Benign

0.75

Sift4G

Benign

0.35

Polyphen

0.0020

Vest4

0.027

MutPred

0.18

Gain of phosphorylation at P879 (P = 0.0187);

MVP

0.54

MPC

0.40

ClinPred

0.017

GERP RS

4.1

Varity_R

0.069

gMVP

0.20

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