1-155284025-C-T

Variant names:

• chr1-155284025-C-T
• rs750317134
• NM_020897.3:c.760C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020897.3(HCN3):​c.760C>T​(p.Leu254Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L254I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN3 NM_020897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 0 publications found

Genes affected

HCN3 (HGNC:19183): (hyperpolarization activated cyclic nucleotide gated potassium channel 3) This gene encodes a multi-pass membrane protein that functions as a voltage gated cation channel. The encoded protein is a member of a family of closely related cyclic adenosine monophosphate-binding channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020897.3. 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
	HCN3	NM_020897.3	MANE Select	c.760C>T	p.Leu254Phe	missense	Exon 3 of 8	NP_065948.1	Q9P1Z3
	HCN3	NR_073074.2		n.888C>T		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN3	ENST00000368358.4	TSL:1 MANE Select	c.760C>T	p.Leu254Phe	missense	Exon 3 of 8	ENSP00000357342.3	Q9P1Z3
	HCN3	ENST00000967752.1		c.760C>T	p.Leu254Phe	missense	Exon 3 of 8	ENSP00000637811.1
	HCN3	ENST00000967751.1		c.760C>T	p.Leu254Phe	missense	Exon 3 of 7	ENSP00000637810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Benign	0.066	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.42
gMVP		0.89
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750317134; hg19: chr1-155253816;