rs55978915

Variant names:

• chr19-610412-C-T
• rs55978915
• NM_001194.4:c.1584+7C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-610412-C-T
• chr19-610412-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0380
• Publications: 1 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]

ENSG00000306481 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 402923.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1932 AD gene.

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.1584+7C>T		splice_region intron	N/A	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.1584+7C>T		splice_region intron	N/A	ENSP00000251287.1	Q9UL51
	ENSG00000306481	ENST00000818911.1		n.349G>A		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.0139 AC: 3431 AN: 247182 AF XY: 0.0134

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 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

African (AFR) AF: 0.00275 AC: 92 AN: 33418

American (AMR) AF: 0.0116 AC: 518 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 389 AN: 26010

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00206 AC: 177 AN: 86114

European-Finnish (FIN) AF: 0.0218 AC: 1151 AN: 52708

Middle Eastern (MID) AF: 0.000900 AC: 5 AN: 5558

European-Non Finnish (NFE) AF: 0.0202 AC: 22475 AN: 1110404

Other (OTH) AF: 0.0143 AC: 861 AN: 60228

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

African (AFR) AF: 0.00286 AC: 119 AN: 41576

American (AMR) AF: 0.00849 AC: 130 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0199 AC: 1353 AN: 68004

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	HCN2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Uncertain	0.98
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs55978915; hg19: chr19-610412;