19-590052-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001194.4(HCN2):c.107C>T(p.Pro36Leu) 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (73 hom., cov: 20)
  • Exomes 𝑓: 0.017 (101 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.272

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018992722).
• BP6: Variant 19-590052-C-T is Benign according to our data. Variant chr19-590052-C-T is described in ClinVar as [Benign]. Clinvar id is 2343084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0269 (3564/132590) while in subpopulation AMR AF= 0.0361 (502/13900). AF 95% confidence interval is 0.0335. There are 73 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd at 3568 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4	c.107C>T	p.Pro36Leu	missense_variant	1/8	ENST00000251287.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN2	ENST00000251287.3	c.107C>T	p.Pro36Leu	missense_variant	1/8	1	NM_001194.4	P1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 3568 AN: 132614 Hom.: 74 Cov.: 20

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.0361

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0552

Gnomad EAS AF: 0.000469

Gnomad SAS AF: 0.00939

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0920

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0326

GnomAD4 exome AF: 0.0166 AC: 8433 AN: 508956 Hom.: 101 Cov.: 6 AF XY: 0.0164 AC XY: 3909 AN XY: 238114

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.0448

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00708

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0269 AC: 3564 AN: 132590 Hom.: 73 Cov.: 20 AF XY: 0.0270 AC XY: 1743 AN XY: 64438

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0552

Gnomad4 EAS AF: 0.000471

Gnomad4 SAS AF: 0.00944

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0257

Gnomad4 OTH AF: 0.0325

Alfa AF: 0.00429 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.079	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.87	P
Vest4		0.24
MutPred		0.31		Loss of glycosylation at P36 (P = 8e-04);
MVP		0.86
MPC		1.5
ClinPred		0.16	T
Varity_R		0.066
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs866177625; hg19: chr19-590052;