rs140235085

chr5-45396681-G-A

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.1041C>T(p.Tyr347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,613,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: HCN1 NM_021072.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.44

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=-0.6).
• BP6: Variant 5-45396681-G-A is Benign according to our data. Variant chr5-45396681-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00023 (35/152208) while in subpopulation EAS AF= 0.00502 (26/5180). AF 95% confidence interval is 0.00352. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.1041C>T	p.Tyr347=	synonymous_variant	4/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.1041C>T	p.Tyr347=	synonymous_variant	4/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.1041C>T	p.Tyr347=	synonymous_variant	4/9			A2
HCN1	ENST00000637305.1	n.204C>T		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000379 AC: 95 AN: 250568 Hom.: 1 AF XY: 0.000436 AC XY: 59 AN XY: 135404

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00349

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000453 AC: 662 AN: 1461466 Hom.: 1 Cov.: 32 AF XY: 0.000455 AC XY: 331 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74418

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000981 Hom.: 0

Bravo AF: 0.000242

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2017

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 24, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

HCN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.72
Dann	Benign	0.52

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: rs140235085; hg19: chr5-45396783;