19-616136-G-C

Variant names:

• chr19-616136-G-C
• rs1060499864
• NM_001194.4:c.2332G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001194.4(HCN2):​c.2332G>C​(p.Ala778Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32160085).

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.2332G>C	p.Ala778Pro	missense	Exon 8 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.2332G>C	p.Ala778Pro	missense	Exon 8 of 8	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.0000576 AC: 1 AN: 17372 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000226

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000598 AC: 141 AN: 235736 Hom.: 0 Cov.: 5 AF XY: 0.000641 AC XY: 70 AN XY: 109256

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

African (AFR) AF: 0.000439 AC: 2 AN: 4556

American (AMR) AF: 0.00 AC: 0 AN: 324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1464

East Asian (EAS) AF: 0.00 AC: 0 AN: 976

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 82

Middle Eastern (MID) AF: 0.00223 AC: 1 AN: 448

European-Non Finnish (NFE) AF: 0.000599 AC: 129 AN: 215434

Other (OTH) AF: 0.00103 AC: 8 AN: 7792

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000575 AC: 1 AN: 17394 Hom.: 0 Cov.: 0 AF XY: 0.000119 AC XY: 1 AN XY: 8388

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

African (AFR) AF: 0.000225 AC: 1 AN: 4436

American (AMR) AF: 0.00 AC: 0 AN: 1474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 392

East Asian (EAS) AF: 0.00 AC: 0 AN: 804

South Asian (SAS) AF: 0.00 AC: 0 AN: 680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8476

Other (OTH) AF: 0.00 AC: 0 AN: 214

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.62
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.63	P
Vest4		0.14
MVP		0.76
MPC		1.4
ClinPred		0.35	T
GERP RS		1.0
Varity_R		0.065
gMVP		0.58
Mutation Taster		=90/10	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: rs1060499864; hg19: chr19-616136;