rs1444972054

Variant names:

• chr5-45645418-T-C
• rs1444972054
• NM_021072.4:c.616A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021072.4(HCN1):​c.616A>G​(p.Ile206Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25997353).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.616A>G	p.Ile206Val	missense	Exon 2 of 8	NP_066550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.616A>G	p.Ile206Val	missense	Exon 2 of 8	ENSP00000307342.4
	HCN1	ENST00000947598.1		c.616A>G	p.Ile206Val	missense	Exon 2 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.616A>G	p.Ile206Val	missense	Exon 2 of 9	ENSP00000501107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250874 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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461404 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.0026
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Benign	0.14	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.46
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Polyphen		0.17	B
Vest4		0.33
MutPred		0.44		Loss of sheet (P = 0.0817)
MVP		0.91
MPC		2.5
ClinPred		0.46	T
GERP RS		5.4
Varity_R		0.27
gMVP		0.82
Mutation Taster		=50/50

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: rs1444972054; hg19: chr5-45645520;