chr5-45396521-C-T

Position:

• chr5-45396521-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_021072.4(HCN1):​c.1201G>A​(p.Asp401Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PP5: Variant 5-45396521-C-T is Pathogenic according to our data. Variant chr5-45396521-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1514590.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN1	NM_021072.4	c.1201G>A	p.Asp401Asn	missense_variant	4/8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.1201G>A	p.Asp401Asn	missense_variant	4/8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.1201G>A	p.Asp401Asn	missense_variant	4/9			ENSP00000501107.1
HCN1	ENST00000637305.1	n.364G>A		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asp401 amino acid residue in HCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24747641). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with clinical features of HCN1-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 401 of the HCN1 protein (p.Asp401Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.58
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.22	B
Vest4		0.74
MutPred		0.40		Gain of MoRF binding (P = 0.0344);
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.70
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-45396623; COSMIC: COSV57529077;