5-45645333-T-C

Variant names:

• chr5-45645333-T-C
• rs1554037381
• NM_021072.4:c.701A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_021072.4(HCN1):​c.701A>G​(p.Tyr234Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y234F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-45645333-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 461375.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 5-45645333-T-C is Pathogenic according to our data. Variant chr5-45645333-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3366984.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.701A>G	p.Tyr234Cys	missense_variant	Exon 2 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.701A>G	p.Tyr234Cys	missense_variant	Exon 2 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.701A>G	p.Tyr234Cys	missense_variant	Exon 2 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.701A>G	p.Tyr234Cys	missense_variant	Exon 2 of 2	3		ENSP00000489134.1
HCN1	ENST00000637256.1	n.-72A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 21, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM2, PM5, PP2, PP3; Variant was found in heterozygous state. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.4	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;T
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.56		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.97
Mutation Taster		=6/94	disease causing

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: rs1554037381; hg19: chr5-45645435;