rs180790607

Variant names:

• chr5-45303695-C-A
• rs180790607
• NM_021072.4:c.1522G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-45303695-C-A
• chr5-45303695-C-G
• chr5-45303695-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_021072.4(HCN1):​c.1522G>T​(p.Val508Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,382 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2805975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.1522G>T	p.Val508Leu	missense_variant	Exon 6 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.1522G>T	p.Val508Leu	missense_variant	Exon 6 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.1522G>T	p.Val508Leu	missense_variant	Exon 6 of 9			ENSP00000501107.1
HCN1	ENST00000637305.1	n.685G>T		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461382 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726984

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Dec 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with leucine at codon 508 of the HCN1 protein (p.Val508Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HCN1-related conditions. 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. 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. -

not provided Uncertain:1

Oct 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.097
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	-0.51	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.29	T
Sift4G	Benign	0.13	T
Polyphen		0.0030	B
Vest4		0.42
MutPred		0.50		Loss of methylation at K510 (P = 0.0865);
MVP		0.96
MPC		2.7
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.69

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

Other links and lift over

dbSNP: rs180790607; hg19: chr5-45303797; COSMIC: COSV57495369;