rs1554040148

Variant names:

• chr5-45696069-A-G
• rs1554040148
• NM_021072.4:c.25T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-45696069-A-G
• chr5-45696069-A-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_021072.4(HCN1):​c.25T>C​(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,204 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S9S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51
• 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: Orphanet, ClinGen
• 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28020924).
• BP6: Variant 5-45696069-A-G is Benign according to our data. Variant chr5-45696069-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 530572.Status of the report is criteria_provided_single_submitter, 1 stars.

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.25T>C	p.Ser9Pro	missense	Exon 1 of 8	NP_066550.2	O60741

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.25T>C	p.Ser9Pro	missense	Exon 1 of 8	ENSP00000307342.4	O60741
	HCN1	ENST00000947598.1		c.25T>C	p.Ser9Pro	missense	Exon 1 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.25T>C	p.Ser9Pro	missense	Exon 1 of 9	ENSP00000501107.1	A0A669KB45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.32e-7 AC: 1 AN: 1202204 Hom.: 0 Cov.: 32 AF XY: 0.00000169 AC XY: 1 AN XY: 592086

African (AFR) AF: 0.00 AC: 0 AN: 24022

American (AMR) AF: 0.0000444 AC: 1 AN: 22512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18826

East Asian (EAS) AF: 0.00 AC: 0 AN: 21030

South Asian (SAS) AF: 0.00 AC: 0 AN: 63436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974234

Other (OTH) AF: 0.00 AC: 0 AN: 46464

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.096
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		0.84	P
Vest4		0.13
MutPred		0.13		Loss of phosphorylation at S9 (P = 0.0054)
MVP		0.82
MPC		2.2
ClinPred		0.43	T
GERP RS		3.2
PromoterAI		0.051	Neutral
Varity_R		0.22
gMVP		0.49
Mutation Taster		=76/24	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: rs1554040148; hg19: chr5-45696171;