19-590037-C-G

Variant names:

• chr19-590037-C-G
• rs1213988839
• NM_001194.4:c.92C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001194.4(HCN2):​c.92C>G​(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17565683).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000617 (3/486278) while in subpopulation SAS AF = 0.000206 (2/9694). AF 95% confidence interval is 0.000036. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 6. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.92C>G	p.Pro31Arg	missense	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.92C>G	p.Pro31Arg	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.00000753 AC: 1 AN: 132850 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000269

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 AF: 0.00000617 AC: 3 AN: 486278 Hom.: 0 Cov.: 6 AF XY: 0.00000878 AC XY: 2 AN XY: 227702

African (AFR) AF: 0.00 AC: 0 AN: 9314

American (AMR) AF: 0.00 AC: 0 AN: 592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3052

East Asian (EAS) AF: 0.00 AC: 0 AN: 2072

South Asian (SAS) AF: 0.000206 AC: 2 AN: 9694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 958

European-Non Finnish (NFE) AF: 0.00000225 AC: 1 AN: 444742

Other (OTH) AF: 0.00 AC: 0 AN: 15704

GnomAD4 genome AF: 0.00000753 AC: 1 AN: 132850 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 64464

African (AFR) AF: 0.0000269 AC: 1 AN: 37114

American (AMR) AF: 0.00 AC: 0 AN: 13956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3234

East Asian (EAS) AF: 0.00 AC: 0 AN: 4272

South Asian (SAS) AF: 0.00 AC: 0 AN: 4336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60294

Other (OTH) AF: 0.00 AC: 0 AN: 1830

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.25	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.64	P
Vest4		0.13
MutPred		0.23		Loss of glycosylation at P31 (P = 0.0111)
MVP		0.47
MPC		1.6
ClinPred		0.13	T
GERP RS		1.1
PromoterAI		-0.017	Neutral
Varity_R		0.098
gMVP		0.22
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: rs1213988839; hg19: chr19-590037;