19-593018-A-G

Variant names:

• chr19-593018-A-G
• rs12977194
• NM_001194.4:c.632+2441A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001194.4(HCN2):​c.632+2441A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,958 control chromosomes in the GnomAD database, including 7,729 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7729 hom., cov: 32)
• Consequence: HCN2 NM_001194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.909
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	NM_001194.4	MANE Select	c.632+2441A>G		intron	N/A	NP_001185.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.632+2441A>G		intron	N/A	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44916 AN: 151840 Hom.: 7703 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.271

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.296 AC: 44991 AN: 151958 Hom.: 7729 Cov.: 32 AF XY: 0.292 AC XY: 21717 AN XY: 74270

African (AFR) AF: 0.479 AC: 19843 AN: 41410

American (AMR) AF: 0.289 AC: 4422 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 763 AN: 3470

East Asian (EAS) AF: 0.0570 AC: 293 AN: 5144

South Asian (SAS) AF: 0.259 AC: 1250 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2119 AN: 10590

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15442 AN: 67936

Other (OTH) AF: 0.270 AC: 569 AN: 2106

Alfa AF: 0.247 Hom.: 2053

Bravo AF: 0.311

Asia WGS AF: 0.184 AC: 641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.62
DANN	Benign	0.72
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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: rs12977194; hg19: chr19-593018;