5-45696069-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 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 (★).

• 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

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 0 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=0.28020924).
• 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 id is 530572.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.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 2	3		ENSP00000489134.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000444

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.46	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.90	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.42	N;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.15	T;T
Polyphen		0.84	P;.
Vest4		0.13
MutPred		0.13		Loss of phosphorylation at S9 (P = 0.0054);Loss of phosphorylation at S9 (P = 0.0054);
MVP		0.82
MPC		2.2
ClinPred		0.43	T
GERP RS		3.2
Varity_R		0.22
gMVP		0.49

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: rs1554040148; hg19: chr5-45696171;