19-590035-C-T

Variant names:

• chr19-590035-C-T
• rs1272239013
• NM_001194.4:c.90C>T
• HCN2 p.Pro30Pro

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001194.4(HCN2):​c.90C>T​(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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: HCN2 NM_001194.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-590035-C-T is Benign according to our data. Variant chr19-590035-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1765791.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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>T	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>T	p.Pro30Pro	synonymous	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000864 AC: 4 AN: 463038 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 217070

⚠️ 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: 0.00000945 AC: 4 AN: 423394

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

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		-0.60
PromoterAI		-0.021	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1272239013; hg19: chr19-590035;