rs745344977

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP2BP4_ModerateBP6_ModerateBS2

The ENST00000303230.6(HCN1):​c.2047C>A​(p.Pro683Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,820 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P683L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HCN1
ENST00000303230.6 missense

Scores

9
10

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.65
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HCN1. . Gene score misZ 3.6647 (greater than the threshold 3.09). Trascript score misZ 3.2427 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.19452107).
BP6
Variant 5-45262547-G-T is Benign according to our data. Variant chr5-45262547-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 530459.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HCN1NM_021072.4 linkuse as main transcriptc.2047C>A p.Pro683Thr missense_variant 8/8 ENST00000303230.6 NP_066550.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HCN1ENST00000303230.6 linkuse as main transcriptc.2047C>A p.Pro683Thr missense_variant 8/81 NM_021072.4 ENSP00000307342 P2
HCN1ENST00000673735.1 linkuse as main transcriptc.*272C>A 3_prime_UTR_variant 9/9 ENSP00000501107 A2
HCN1ENST00000637305.1 linkuse as main transcriptn.1210C>A non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461820
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Uncertain
0.040
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
T
Eigen
Benign
0.038
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.19
T
MetaSVM
Uncertain
0.67
D
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
0.84
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0070
D
Sift4G
Benign
0.082
T
Polyphen
0.0020
B
Vest4
0.25
MutPred
0.47
Gain of phosphorylation at P683 (P = 0.0502);
MVP
0.50
MPC
0.43
ClinPred
0.52
D
GERP RS
5.4
Varity_R
0.32
gMVP
0.46

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.

Other links and lift over

dbSNP: rs745344977; hg19: chr5-45262649; API