19-607984-G-C

Variant names:

• chr19-607984-G-C
• rs3752158
• NM_001194.4:c.1239G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001194.4(HCN2):​c.1239G>C​(p.Leu413Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,612,052 control chromosomes in the GnomAD database, including 6,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L413L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1367 hom., cov: 33)
  • Exomes 𝑓: 0.074 (4913 hom.)
• Consequence: HCN2 NM_001194.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-607984-G-C is Benign according to our data. Variant chr19-607984-G-C is described in ClinVar as Benign. ClinVar VariationId is 1226607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 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.1239G>C	p.Leu413Leu	synonymous	Exon 4 of 8	NP_001185.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.1239G>C	p.Leu413Leu	synonymous	Exon 4 of 8	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17669 AN: 152150 Hom.: 1364 Cov.: 33

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0643

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0932 AC: 23170 AN: 248694 AF XY: 0.0893

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.0866

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0903

GnomAD4 exome AF: 0.0743 AC: 108479 AN: 1459784 Hom.: 4913 Cov.: 32 AF XY: 0.0743 AC XY: 53961 AN XY: 726250

African (AFR) AF: 0.217 AC: 7242 AN: 33450

American (AMR) AF: 0.126 AC: 5654 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 2192 AN: 26128

East Asian (EAS) AF: 0.134 AC: 5325 AN: 39684

South Asian (SAS) AF: 0.0920 AC: 7928 AN: 86208

European-Finnish (FIN) AF: 0.0635 AC: 3321 AN: 52320

Middle Eastern (MID) AF: 0.105 AC: 545 AN: 5210

European-Non Finnish (NFE) AF: 0.0641 AC: 71231 AN: 1111764

Other (OTH) AF: 0.0836 AC: 5041 AN: 60320

GnomAD4 genome AF: 0.116 AC: 17709 AN: 152268 Hom.: 1367 Cov.: 33 AF XY: 0.118 AC XY: 8759 AN XY: 74436

African (AFR) AF: 0.210 AC: 8732 AN: 41538

American (AMR) AF: 0.136 AC: 2074 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 305 AN: 3472

East Asian (EAS) AF: 0.132 AC: 684 AN: 5164

South Asian (SAS) AF: 0.0903 AC: 436 AN: 4828

European-Finnish (FIN) AF: 0.0671 AC: 713 AN: 10620

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0643 AC: 4375 AN: 68022

Other (OTH) AF: 0.102 AC: 215 AN: 2112

Alfa AF: 0.0453 Hom.: 49

Bravo AF: 0.124

EpiCase AF: 0.0717

EpiControl AF: 0.0695

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.22
DANN	Benign	0.77
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3752158; hg19: chr19-607984; COSMIC: COSV52114904;