rs1213988839

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-590037-C-A
• chr19-590037-C-G
• chr19-590037-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_001194.4(HCN2):​c.92C>A​(p.Pro31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. P31R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000082 (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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20293239).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000823 (4/486268) while in subpopulation AFR AF = 0.000215 (2/9312). AF 95% confidence interval is 0.0000374. 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.

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>A	p.Pro31His	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>A	p.Pro31His	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000823 AC: 4 AN: 486268 Hom.: 0 Cov.: 6 AF XY: 0.00000878 AC XY: 2 AN XY: 227700

African (AFR) AF: 0.000215 AC: 2 AN: 9312

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: 0.00 AC: 0 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: 0.00000450 AC: 2 AN: 444734

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

GnomAD4 genome Cov.: 20

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	0.18
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.20	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	0.55	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.84	P
Vest4		0.14
MutPred		0.23		Loss of glycosylation at P31 (P = 0.0111)
MVP		0.49
MPC		1.7
ClinPred		0.15	T
GERP RS		1.1
PromoterAI		-0.013	Neutral
Varity_R		0.15
gMVP		0.24
Mutation Taster		=89/11	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;