19-590007-GGCC-G

Variant names:

• chr19-590007-GGCC-G
• rs961585316
• NM_001194.4:c.81_83delGCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PM4_Supporting BP6_Moderate

The NM_001194.4(HCN2):​c.81_83delGCC​(p.Pro28del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 637,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: HCN2 NM_001194.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.460
• Publications: 0 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: Likely_benign. The variant received -1 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-GGCC-G is Benign according to our data. Variant chr19-590007-GGCC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3283623.Status of the report is criteria_provided_single_submitter, 1 stars.

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.81_83delGCC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 8	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.81_83delGCC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.0000157 AC: 2 AN: 127068 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000172

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00236 AC: 1202 AN: 510382 Hom.: 0 AF XY: 0.00242 AC XY: 577 AN XY: 238880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00207 AC: 20 AN: 9666

American (AMR) AF: 0.00469 AC: 3 AN: 640

Ashkenazi Jewish (ASJ) AF: 0.00190 AC: 6 AN: 3158

East Asian (EAS) AF: 0.00182 AC: 4 AN: 2202

South Asian (SAS) AF: 0.00275 AC: 28 AN: 10168

European-Finnish (FIN) AF: 0.00610 AC: 1 AN: 164

Middle Eastern (MID) AF: 0.00412 AC: 4 AN: 970

European-Non Finnish (NFE) AF: 0.00235 AC: 1097 AN: 466900

Other (OTH) AF: 0.00236 AC: 39 AN: 16514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000157 AC: 2 AN: 127068 Hom.: 0 Cov.: 20 AF XY: 0.0000162 AC XY: 1 AN XY: 61640

African (AFR) AF: 0.0000282 AC: 1 AN: 35426

American (AMR) AF: 0.00 AC: 0 AN: 13496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3146

East Asian (EAS) AF: 0.00 AC: 0 AN: 3798

South Asian (SAS) AF: 0.00 AC: 0 AN: 3850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000172 AC: 1 AN: 58270

Other (OTH) AF: 0.00 AC: 0 AN: 1748

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=82/18	polymorphism

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: rs961585316; hg19: chr19-590007;