rs587777494

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_021072.4(HCN1):​c.890G>C​(p.Arg297Thr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

HCN1
NM_021072.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90
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_pathogenic. Variant got 6 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). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 59 curated benign missense variants. GenCC has associacion of the 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.935
PP5
Variant 5-45461967-C-G is Pathogenic according to our data. Variant chr5-45461967-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 139574.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HCN1NM_021072.4 linkc.890G>C p.Arg297Thr missense_variant 3/8 ENST00000303230.6 NP_066550.2 O60741Q86WJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HCN1ENST00000303230.6 linkc.890G>C p.Arg297Thr missense_variant 3/81 NM_021072.4 ENSP00000307342.4 O60741
HCN1ENST00000673735.1 linkc.890G>C p.Arg297Thr missense_variant 3/9 ENSP00000501107.1 A0A669KB45
HCN1ENST00000637305.1 linkn.53G>C non_coding_transcript_exon_variant 2/75

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 24 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-5.5
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.87
P
Vest4
0.97
MutPred
0.70
Gain of glycosylation at R297 (P = 0.0891);
MVP
0.99
MPC
3.4
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.94
gMVP
0.99

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: rs587777494; hg19: chr5-45462069; COSMIC: COSV57508227; API