NM_001194.4:c.253C>T

Variant names:

• chr19-590198-C-T
• NM_001194.4:c.253C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001194.4(HCN2):​c.253C>T​(p.Pro85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 838,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250
• Publications: 0 publications found

Genes affected

HCN2 (HGNC:4846): (hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2) The protein encoded by this gene is a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and in the brain. The encoded protein is activated by cAMP and can produce a fast, large current. Defects in this gene were noted as a possible cause of some forms of epilepsy. [provided by RefSeq, Jan 2017]

ENSG00000267036 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.151173).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194.4. 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
	HCN2	NM_001194.4	MANE Select	c.253C>T	p.Pro85Ser	missense	Exon 1 of 8	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.253C>T	p.Pro85Ser	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51
	ENSG00000267036	ENST00000589661.2	TSL:6	n.*232G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000358 AC: 3 AN: 838622 Hom.: 0 Cov.: 29 AF XY: 0.00000515 AC XY: 2 AN XY: 388432

African (AFR) AF: 0.00 AC: 0 AN: 15852

American (AMR) AF: 0.00 AC: 0 AN: 1106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5242

East Asian (EAS) AF: 0.00 AC: 0 AN: 3746

South Asian (SAS) AF: 0.00 AC: 0 AN: 17520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1646

European-Non Finnish (NFE) AF: 0.00000392 AC: 3 AN: 765472

Other (OTH) AF: 0.00 AC: 0 AN: 27528

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.025
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.14	T
Polyphen		0.049	B
Vest4		0.030
MutPred		0.17		Gain of phosphorylation at P85 (P = 0.0069)
MVP		0.76
MPC		1.5
ClinPred		0.053	T
PromoterAI		-0.026	Neutral
Varity_R		0.052
gMVP		0.23
Mutation Taster		=90/10	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

hg19: chr19-590198;