19-590052-C-T

Variant names:

• chr19-590052-C-T
• rs866177625
• NM_001194.4:c.107C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.272
• Publications: 1 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: Benign. The variant received -20 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/Likely_benign. ClinVar VariationId is 2343084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3564 AD gene.

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.107C>T	p.Pro36Leu	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.107C>T	p.Pro36Leu	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

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

African (AFR) AF: 0.0212 AC: 208 AN: 9824

American (AMR) AF: 0.0228 AC: 14 AN: 614

Ashkenazi Jewish (ASJ) AF: 0.0448 AC: 139 AN: 3100

East Asian (EAS) AF: 0.00 AC: 0 AN: 2204

South Asian (SAS) AF: 0.00708 AC: 73 AN: 10314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 162

Middle Eastern (MID) AF: 0.0340 AC: 34 AN: 1000

European-Non Finnish (NFE) AF: 0.0164 AC: 7631 AN: 465454

Other (OTH) AF: 0.0205 AC: 334 AN: 16284

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

African (AFR) AF: 0.0277 AC: 1024 AN: 36960

American (AMR) AF: 0.0361 AC: 502 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 177 AN: 3206

East Asian (EAS) AF: 0.000471 AC: 2 AN: 4242

South Asian (SAS) AF: 0.00944 AC: 40 AN: 4238

European-Finnish (FIN) AF: 0.0237 AC: 163 AN: 6872

Middle Eastern (MID) AF: 0.0893 AC: 20 AN: 224

European-Non Finnish (NFE) AF: 0.0257 AC: 1549 AN: 60356

Other (OTH) AF: 0.0325 AC: 60 AN: 1844

Alfa AF: 0.00429 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.27
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
PromoterAI		-0.020	Neutral
Varity_R		0.066
gMVP		0.24
Mutation Taster		=87/13	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: rs866177625; hg19: chr19-590052;