1-155282760-G-C

Variant names:

• chr1-155282760-G-C
• NM_020897.3:c.628G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020897.3(HCN3):​c.628G>C​(p.Val210Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN3 NM_020897.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN3	NM_020897.3	c.628G>C	p.Val210Leu	missense_variant	Exon 2 of 8	ENST00000368358.4	NP_065948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN3	ENST00000368358.4	c.628G>C	p.Val210Leu	missense_variant	Exon 2 of 8	1	NM_020897.3	ENSP00000357342.3
HCN3	ENST00000467204.1	n.223G>C		non_coding_transcript_exon_variant	Exon 1 of 5	5
HCN3	ENST00000496230.5	n.520G>C		non_coding_transcript_exon_variant	Exon 2 of 8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628G>C (p.V210L) alteration is located in exon 2 (coding exon 2) of the HCN3 gene. This alteration results from a G to C substitution at nucleotide position 628, causing the valine (V) at amino acid position 210 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.53	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.60
Sift	Benign	0.79	T
Sift4G	Benign	0.54	T
Polyphen		0.019	B
Vest4		0.87
MutPred		0.53		Loss of MoRF binding (P = 0.1266);
MVP		0.94
MPC		0.63
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155252551;