chr19-590187-C-T

Variant names:

• chr19-590187-C-T
• rs1187246548
• NM_001194.4:c.242C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_001194.4(HCN2):​c.242C>T​(p.Ser81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 143,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S81W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.353
• 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]

ENSG00000267036 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15096852).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000209 (3/143838) while in subpopulation NFE AF = 0.0000463 (3/64820). AF 95% confidence interval is 0.0000123. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 29. 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.242C>T	p.Ser81Leu	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.242C>T	p.Ser81Leu	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51
	ENSG00000267036	ENST00000589661.2	TSL:6	n.*243G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000209 AC: 3 AN: 143838 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000463

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 837390 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 387754

African (AFR) AF: 0.00 AC: 0 AN: 15830

American (AMR) AF: 0.00 AC: 0 AN: 1070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5204

East Asian (EAS) AF: 0.00 AC: 0 AN: 3728

South Asian (SAS) AF: 0.00 AC: 0 AN: 17380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 764628

Other (OTH) AF: 0.00 AC: 0 AN: 27474

GnomAD4 genome AF: 0.0000209 AC: 3 AN: 143838 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 69906

African (AFR) AF: 0.00 AC: 0 AN: 40148

American (AMR) AF: 0.00 AC: 0 AN: 14626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000463 AC: 3 AN: 64820

Other (OTH) AF: 0.00 AC: 0 AN: 1984

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.35
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.27
Sift	Benign	0.033	D
Sift4G	Benign	0.31	T
Polyphen		0.032	B
Vest4		0.084
MutPred		0.24		Loss of phosphorylation at S81 (P = 0.0015)
MVP		0.70
MPC		1.4
ClinPred		0.10	T
PromoterAI		0.039	Neutral
Varity_R		0.12
gMVP		0.21
Mutation Taster		=95/5	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: rs1187246548; hg19: chr19-590187;