rs779788281

chr5-45695893-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021072.4(HCN1):c.201T>C(p.Gly67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,444,832 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G67G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: HCN1 NM_021072.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-45695893-A-G is Benign according to our data. Variant chr5-45695893-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 412770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000219 (30/136974) while in subpopulation AFR AF= 0.000664 (23/34664). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.201T>C	p.Gly67=	synonymous_variant	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.201T>C	p.Gly67=	synonymous_variant	1/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.201T>C	p.Gly67=	synonymous_variant	1/9			A2
HCN1	ENST00000634658.1	c.201T>C	p.Gly67=	synonymous_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000219 AC: 30 AN: 136856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000222

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000949

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000142 AC: 17 AN: 120082 Hom.: 0 AF XY: 0.000135 AC XY: 9 AN XY: 66606

Gnomad AFR exome AF: 0.000761

Gnomad AMR exome AF: 0.0000519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000212

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 134 AN: 1307858 Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 68 AN XY: 645300

Gnomad4 AFR exome AF: 0.000722

Gnomad4 AMR exome AF: 0.0000337

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000231

Gnomad4 SAS exome AF: 0.0000832

Gnomad4 FIN exome AF: 0.0000844

Gnomad4 NFE exome AF: 0.0000857

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000219 AC: 30 AN: 136974 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 9 AN XY: 67222

Gnomad4 AFR AF: 0.000664

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000223

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000949

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000927 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

HCN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
Dann	Benign	0.55

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: rs779788281; hg19: chr5-45695995; COSMIC: COSV57495191; COSMIC: COSV57495191;