rs55978915

chr19-610412-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001194.4(HCN2):c.1584+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,611,018 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 33)
  • Exomes 𝑓: 0.018 (271 hom.)
• Consequence: HCN2 NM_001194.4 splice_region, intron
• Scores: Splicing: ADA: 0.009542
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380

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]

LOC107987266 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-610412-C-T is Benign according to our data. Variant chr19-610412-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-610412-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1932/152292) while in subpopulation NFE AF= 0.0199 (1353/68004). AF 95% confidence interval is 0.019. There are 22 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1932 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4	c.1584+7C>T		splice_region_variant, intron_variant		ENST00000251287.3
LOC107987266	XR_001753828.2	n.1338G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN2	ENST00000251287.3	c.1584+7C>T		splice_region_variant, intron_variant		1	NM_001194.4	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1932 AN: 152174 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0139 AC: 3431 AN: 247182 Hom.: 31 AF XY: 0.0134 AC XY: 1799 AN XY: 134340

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0176 AC: 25670 AN: 1458726 Hom.: 271 Cov.: 32 AF XY: 0.0171 AC XY: 12377 AN XY: 725686

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0127 AC: 1932 AN: 152292 Hom.: 22 Cov.: 33 AF XY: 0.0127 AC XY: 946 AN XY: 74452

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0170 Hom.: 17

Bravo AF: 0.0114

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.0177

EpiControl AF: 0.0167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 168/13002=1.2% -

HCN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	10
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0095
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55978915; hg19: chr19-610412;