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5-45303695-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP5BP4BS2

The NM_021072.4(HCN1):​c.1522G>A​(p.Val508Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,562 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

1
12
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.03
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant where missense usually causes diseases, HCN1
PP5
Variant 5-45303695-C-T is Pathogenic according to our data. Variant chr5-45303695-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530453.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.28817433). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HCN1NM_021072.4 linkuse as main transcriptc.1522G>A p.Val508Met missense_variant 6/8 ENST00000303230.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HCN1ENST00000303230.6 linkuse as main transcriptc.1522G>A p.Val508Met missense_variant 6/81 NM_021072.4 P2
HCN1ENST00000673735.1 linkuse as main transcriptc.1522G>A p.Val508Met missense_variant 6/9 A2
HCN1ENST00000637305.1 linkuse as main transcriptn.685G>A non_coding_transcript_exon_variant 5/75

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152062
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
250768
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135500
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000452
AC:
66
AN:
1461382
Hom.:
0
Cov.:
32
AF XY:
0.0000385
AC XY:
28
AN XY:
726984
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 19, 2023This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 508 of the HCN1 protein (p.Val508Met). This variant is present in population databases (rs180790607, gnomAD 0.01%). This missense change has been observed in individuals with HCN1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 530453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.033
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.92
D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.29
T
MetaSVM
Uncertain
0.51
D
MutationAssessor
Benign
1.0
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.9
N
REVEL
Uncertain
0.52
Sift
Benign
0.069
T
Sift4G
Uncertain
0.038
D
Polyphen
0.75
P
Vest4
0.46
MVP
0.90
MPC
2.7
ClinPred
0.15
T
GERP RS
5.6
Varity_R
0.22
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs180790607; hg19: chr5-45303797; COSMIC: COSV57501466; API