rs544994462

chr5-45695954-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021072.4(HCN1):c.140G>T(p.Gly47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,332,860 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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. G47R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (26 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.91

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.005699843).
• BP6: Variant 5-45695954-C-A is Benign according to our data. Variant chr5-45695954-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 193442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45695954-C-A is described in Lovd as [Likely_benign]. Variant chr5-45695954-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (523/149920) while in subpopulation NFE AF= 0.00612 (412/67346). AF 95% confidence interval is 0.00563. There are 2 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.140G>T	p.Gly47Val	missense_variant	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.140G>T	p.Gly47Val	missense_variant	1/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.140G>T	p.Gly47Val	missense_variant	1/9			A2
HCN1	ENST00000634658.1	c.140G>T	p.Gly47Val	missense_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 523 AN: 149810 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00252

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.00213

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00612

Gnomad OTH AF: 0.00388

GnomAD3 exomes AF: 0.00661 AC: 143 AN: 21648 Hom.: 1 AF XY: 0.00673 AC XY: 94 AN XY: 13968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00247

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00383

GnomAD4 exome AF: 0.00620 AC: 7333 AN: 1182940 Hom.: 26 Cov.: 32 AF XY: 0.00613 AC XY: 3540 AN XY: 577248

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000768

Gnomad4 FIN exome AF: 0.00287

Gnomad4 NFE exome AF: 0.00707

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00349 AC: 523 AN: 149920 Hom.: 2 Cov.: 32 AF XY: 0.00335 AC XY: 245 AN XY: 73212

Gnomad4 AFR AF: 0.000971

Gnomad4 AMR AF: 0.00252

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000627

Gnomad4 FIN AF: 0.00213

Gnomad4 NFE AF: 0.00612

Gnomad4 OTH AF: 0.00384

Alfa AF: 0.00346 Hom.: 0

Bravo AF: 0.00340

ExAC AF: 0.00177 AC: 27

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 24747641) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HCN1: PP2, PP3, BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2018

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. -

Developmental and epileptic encephalopathy, 24;C5193120:Generalized epilepsy with febrile seizures plus, type 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

HCN1 NM_021072.3 exon 1 p.Gly47Val (c.140G>T):This variant has been reported in the literature in 1 individual with early infantile epileptic encephalopathy (Nava 2014 PMID:24747641). However this variant is present in 0.6% (412/67356) of European alleles including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-45695954-C-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign(Variation ID:193442). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

HCN1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

This variant is classified as 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
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.84	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.20	T;.
Sift4G	Benign	0.27	T;T
Polyphen		0.36	B;.
Vest4		0.17
MVP		0.72
MPC		3.0
ClinPred		0.043	T
GERP RS		3.3
Varity_R		0.075
gMVP		0.31

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: rs544994462; hg19: chr5-45696056; COSMIC: COSV57523921; COSMIC: COSV57523921;