19-590035-C-G

Variant names:

• chr19-590035-C-G
• rs1272239013
• NM_001194.4:c.90C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001194.4(HCN2):​c.90C>G​(p.Pro30Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P30P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN2 NM_001194.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.599
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-0.599 with no splicing effect.

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.90C>G	p.Pro30Pro	synonymous	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.90C>G	p.Pro30Pro	synonymous	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000216 AC: 1 AN: 463040 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 217072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8902

American (AMR) AF: 0.00 AC: 0 AN: 574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2902

East Asian (EAS) AF: 0.00 AC: 0 AN: 1960

South Asian (SAS) AF: 0.00 AC: 0 AN: 9232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 906

European-Non Finnish (NFE) AF: 0.00000236 AC: 1 AN: 423396

Other (OTH) AF: 0.00 AC: 0 AN: 15026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		-0.60
PromoterAI		-0.019	Neutral

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

dbSNP: rs1272239013; hg19: chr19-590035;