5-45695935-G-T

Variant names:

• chr5-45695935-G-T
• rs10066808
• NM_021072.4:c.159C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021072.4(HCN1):​c.159C>A​(p.His53Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,272,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H53Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.971
• Publications: 2 publications found

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]

HCN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• generalized epilepsy with febrile seizures plus, type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11430639).
• BP6: Variant 5-45695935-G-T is Benign according to our data. Variant chr5-45695935-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2724937.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.159C>A	p.His53Gln	missense	Exon 1 of 8	NP_066550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.159C>A	p.His53Gln	missense	Exon 1 of 8	ENSP00000307342.4
	HCN1	ENST00000673735.1		c.159C>A	p.His53Gln	missense	Exon 1 of 9	ENSP00000501107.1
	HCN1	ENST00000634658.1	TSL:3	c.159C>A	p.His53Gln	missense	Exon 1 of 2	ENSP00000489134.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 53536 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000786 AC: 10 AN: 1272462 Hom.: 0 Cov.: 33 AF XY: 0.00000957 AC XY: 6 AN XY: 626906

African (AFR) AF: 0.00 AC: 0 AN: 24754

American (AMR) AF: 0.00 AC: 0 AN: 15788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20474

East Asian (EAS) AF: 0.00 AC: 0 AN: 27792

South Asian (SAS) AF: 0.000156 AC: 10 AN: 64276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1030276

Other (OTH) AF: 0.00 AC: 0 AN: 52206

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 24 Uncertain:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.159C>A(p.His53Gln) in HCN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.159C>A variant has 0 frequency in gnomAD Exomes. Computational evidence (Polyphen, SIFT and MutationTaster) predicts conflicting evidence on protein structure and function for this variant.The amino acid Histidine at position 53 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance.

Developmental and epileptic encephalopathy Benign:1

Dec 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.97
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.27
Sift	Benign	0.33	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.080		Loss of ubiquitination at K51 (P = 0.1055)
MVP		0.62
MPC		2.6
ClinPred		0.16	T
GERP RS		-1.3
PromoterAI		0.013	Neutral
Varity_R		0.071
gMVP		0.68
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs10066808; hg19: chr5-45696037;