5-45261959-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS1

The NM_021072.4(HCN1):c.2635C>T(p.Pro879Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P879T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.11

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.026440263).
• BP6: Variant 5-45261959-G-A is Benign according to our data. Variant chr5-45261959-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1554103.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000752 (11/1461862) while in subpopulation EAS AF= 0.000252 (10/39700). AF 95% confidence interval is 0.000136. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.2635C>T	p.Pro879Ser	missense_variant	8/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.2635C>T	p.Pro879Ser	missense_variant	8/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.*860C>T		3_prime_UTR_variant	9/9			A2
HCN1	ENST00000637305.1	n.1798C>T		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250940 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 12, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Benign	0.82
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.87	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Benign	0.75	T
Sift4G	Benign	0.35	T
Polyphen		0.0020	B
Vest4		0.027
MutPred		0.18		Gain of phosphorylation at P879 (P = 0.0187);
MVP		0.54
MPC		0.40
ClinPred		0.017	T
GERP RS		4.1
Varity_R		0.069
gMVP		0.20

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: rs761866949; hg19: chr5-45262061;