5-45645314-T-G

Variant names:

• chr5-45645314-T-G
• rs1554037379
• NM_021072.4:c.720A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_021072.4(HCN1):​c.720A>C​(p.Glu240Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the HCN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 59 curated benign missense variants. Gene score misZ: 3.6647 (above the threshold of 3.09). Trascript score misZ: 3.2427 (above the threshold of 3.09). GenCC associations: The gene is linked to generalized epilepsy with febrile seizures plus, type 10, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 24, generalized epilepsy with febrile seizures plus.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3843527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.720A>C	p.Glu240Asp	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.720A>C	p.Glu240Asp	missense_variant	Exon 2 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.720A>C	p.Glu240Asp	missense_variant	Exon 2 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.720A>C	p.Glu240Asp	missense_variant	Exon 2 of 2	3		ENSP00000489134.1
HCN1	ENST00000637256.1	n.-53A>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Uncertain:1

Aug 19, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PP2 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.43	N;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.12	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.0060	B;.
Vest4		0.56
MutPred		0.50		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.99
MPC		2.6
ClinPred		0.79	D
GERP RS		3.0
Varity_R		0.26
gMVP		0.95

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: rs1554037379; hg19: chr5-45645416;