19-590316-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001194.4(HCN2):c.371C>T(p.Ser124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 870,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.275

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26319626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4	c.371C>T	p.Ser124Leu	missense_variant	1/8	ENST00000251287.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN2	ENST00000251287.3	c.371C>T	p.Ser124Leu	missense_variant	1/8	1	NM_001194.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000344 AC: 3 AN: 870986 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 406120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: HCN2 c.371C>T (p.Ser124Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 24284 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.371C>T in individuals affected with Familial Febrile Seizures and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.90	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.35
Sift	Benign	0.057	T
Sift4G	Benign	0.17	T
Polyphen		0.89	P
Vest4		0.16
MutPred		0.36		Loss of phosphorylation at S124 (P = 0.0342);
MVP		0.65
MPC		1.4
ClinPred		0.15	T
GERP RS		1.6
Varity_R		0.12
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-590316;