5-45396550-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_021072.4(HCN1):​c.1172G>A​(p.Gly391Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G391S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HCN1
NM_021072.4 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.91
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 Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_021072.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-45396551-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 635189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 5-45396550-C-T is Pathogenic according to our data. Variant chr5-45396550-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN1NM_021072.4 linkc.1172G>A p.Gly391Asp missense_variant Exon 4 of 8 ENST00000303230.6 NP_066550.2 O60741Q86WJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HCN1ENST00000303230.6 linkc.1172G>A p.Gly391Asp missense_variant Exon 4 of 8 1 NM_021072.4 ENSP00000307342.4 O60741
HCN1ENST00000673735.1 linkc.1172G>A p.Gly391Asp missense_variant Exon 4 of 9 ENSP00000501107.1 A0A669KB45
HCN1ENST00000637305.1 linkn.335G>A non_coding_transcript_exon_variant Exon 3 of 7 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 24 Pathogenic:2
Oct 13, 2020
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 01, 2018
NeuroMeGen, Hospital Clinico Santiago de Compostela
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Epileptic encephalopathy Pathogenic:1
Nov 16, 2016
Neurogenetics Laboratory - MEYER, AOU Meyer
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
1.0
MutPred
0.77
Gain of catalytic residue at G391 (P = 0.0499);
MVP
1.0
MPC
3.1
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.99
gMVP
1.0

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: rs1057519547; hg19: chr5-45396652; COSMIC: COSV57494848; API