Genetic Variant NM_021072.4:c.25T>C (chr5-45696069-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4BP6_Moderate

The NM_021072.4(HCN1):c.25T>C(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,204 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.51

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.28020924).

BP6

Variant 5-45696069-A-G is Benign according to our data. Variant chr5-45696069-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 530572.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 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.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 link	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 link	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 2	3		ENSP00000489134.1	A0A0U1RQR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.32e-7

AC:

AN:

1202204

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000444

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:

0.00

GnomAD4 genome

Cov.:

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

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.90

L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.42

N;.

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.15

T;T

Polyphen

0.84

P;.

Vest4

0.13

MutPred

0.13

Loss of phosphorylation at S9 (P = 0.0054);Loss of phosphorylation at S9 (P = 0.0054);

MVP

0.82

MPC

2.2

ClinPred

0.43

GERP RS

3.2

Varity_R

0.22

gMVP

0.49

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