19-590007-G-GGCC

Variant names:

• chr19-590007-G-GGCC
• rs961585316
• NM_001194.4:c.81_83dupGCC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BS1 BS2

The NM_001194.4(HCN2):​c.81_83dupGCC​(p.Pro28dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 20)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: HCN2 NM_001194.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.460

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

Verdict is Benign. Variant got -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001194.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-590007-G-GGCC is Benign according to our data. Variant chr19-590007-G-GGCC is described in ClinVar as [Likely_benign]. Clinvar id is 2357092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000882 (112/127052) while in subpopulation AFR AF= 0.00282 (100/35458). AF 95% confidence interval is 0.00237. There are 1 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN2	NM_001194.4	c.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	Exon 1 of 8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3	c.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_001194.4	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.000866 AC: 110 AN: 127064 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000370

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000527

Gnomad SAS AF: 0.000779

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000343

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 33 AN: 513590 Hom.: 0 Cov.: 4 AF XY: 0.0000499 AC XY: 12 AN XY: 240392

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000977

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000241

GnomAD4 genome AF: 0.000882 AC: 112 AN: 127052 Hom.: 1 Cov.: 20 AF XY: 0.000973 AC XY: 60 AN XY: 61642

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.000370

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000529

Gnomad4 SAS AF: 0.000782

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000343

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs961585316; hg19: chr19-590007;