rs148932124

chr5-45262797-T-C

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.1797A>G(p.Ser599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,613,884 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (30 hom.)
• Consequence: HCN1 NM_021072.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.96

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=-0.59).
• BP6: Variant 5-45262797-T-C is Benign according to our data. Variant chr5-45262797-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 167167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45262797-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00401 (611/152210) while in subpopulation NFE AF= 0.00587 (399/68018). AF 95% confidence interval is 0.00539. There are 4 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 611 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.1797A>G	p.Ser599=	synonymous_variant	8/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.1797A>G	p.Ser599=	synonymous_variant	8/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.*22A>G		3_prime_UTR_variant	9/9			A2
HCN1	ENST00000637305.1	n.960A>G		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 611 AN: 152092 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00390 AC: 973 AN: 249266 Hom.: 3 AF XY: 0.00370 AC XY: 499 AN XY: 134948

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00488 AC: 7126 AN: 1461674 Hom.: 30 Cov.: 32 AF XY: 0.00469 AC XY: 3408 AN XY: 727126

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00798

Gnomad4 NFE exome AF: 0.00550

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00401 AC: 611 AN: 152210 Hom.: 4 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74412

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00520 Hom.: 2

Bravo AF: 0.00350

EpiCase AF: 0.00583

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HCN1: BP4, BP7, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 12, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	7.1
Dann	Benign	0.58

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: rs148932124; hg19: chr5-45262899;