rs1057519548

Variant names:

• chr5-45645575-C-A
• rs1057519548
• NM_021072.4:c.459G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-45645575-C-A
• chr5-45645575-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP5_Moderate

The NM_021072.4(HCN1):​c.459G>T​(p.Met153Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87
• 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 8 ACMG points.

• PS1: Transcript NM_021072.4 (HCN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 375530
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-45645575-C-A is Pathogenic according to our data. Variant chr5-45645575-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1741776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.459G>T	p.Met153Ile	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.459G>T	p.Met153Ile	missense_variant	Exon 2 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.459G>T	p.Met153Ile	missense_variant	Exon 2 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.459G>T	p.Met153Ile	missense_variant	Exon 2 of 2	3		ENSP00000489134.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Nov 02, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M153I variant (also known as c.459G>T), located in coding exon 2 of the HCN1 gene, results from a G to T substitution at nucleotide position 459. The methionine at codon 153 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of epilepsy (Ambry internal data). A different variant (c.459G>C) resulting in the same amino acid substitution has also been reported to be de novo in an individual with early infantile epileptic encephalopathy (Parrini E et al. Hum. Mutat., 2017 Feb;38:216-225). In addition, this amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.6	L;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.16	T;.
Sift4G	Benign	0.082	T;T
Polyphen		0.0	B;.
Vest4		0.74
MutPred		0.60		Gain of catalytic residue at M153 (P = 0.0169);Gain of catalytic residue at M153 (P = 0.0169);
MVP		0.98
MPC		1.7
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.98
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1057519548; hg19: chr5-45645677;