1-155284122-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020897.3(HCN3):c.857T>C(p.Ile286Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: HCN3 NM_020897.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38452405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN3	NM_020897.3	c.857T>C	p.Ile286Thr	missense_variant	3/8	ENST00000368358.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN3	ENST00000368358.4	c.857T>C	p.Ile286Thr	missense_variant	3/8	1	NM_020897.3	P1
HCN3	ENST00000496230.5	n.749T>C		non_coding_transcript_exon_variant	3/8	2
HCN3	ENST00000467204.1	n.304-417T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2022

The c.857T>C (p.I286T) alteration is located in exon 3 (coding exon 3) of the HCN3 gene. This alteration results from a T to C substitution at nucleotide position 857, causing the isoleucine (I) at amino acid position 286 to be replaced by a threonine (T). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.063
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Benign	0.065	T
Sift4G	Benign	0.093	T
Polyphen		0.13	B
Vest4		0.37
MutPred		0.53		Loss of stability (P = 0.0549);
MVP		0.90
MPC		0.69
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.20
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-155253913;