5-45695835-G-T

Position:

• chr5-45695835-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021072.4(HCN1):​c.259C>A​(p.Pro87Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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 1 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=0.20471981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN1	NM_021072.4	c.259C>A	p.Pro87Thr	missense_variant	1/8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.259C>A	p.Pro87Thr	missense_variant	1/8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.259C>A	p.Pro87Thr	missense_variant	1/9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.259C>A	p.Pro87Thr	missense_variant	1/2	3		ENSP00000489134.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450320 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721874

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: 0.0000212

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.65	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	0.34	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.44	N;.
REVEL	Benign	0.24
Sift	Benign	0.20	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.0020	B;.
Vest4		0.14
MutPred		0.20		Gain of phosphorylation at P87 (P = 0.0142);Gain of phosphorylation at P87 (P = 0.0142);
MVP		0.33
MPC		1.6
ClinPred		0.21	T
GERP RS		2.4
Varity_R		0.054
gMVP		0.59

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

Other links and lift over

dbSNP: rs370113959; hg19: chr5-45695937;