rs1060499864

Variant names:

• chr19-616136-G-A
• rs1060499864
• NM_001194.4:c.2332G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-616136-G-A
• chr19-616136-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001194.4(HCN2):​c.2332G>A​(p.Ala778Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. A778P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24323338).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000631 (15/237876) while in subpopulation AMR AF = 0.00309 (1/324). AF 95% confidence interval is 0.0000353. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 5. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 15 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.2332G>A	p.Ala778Thr	missense	Exon 8 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.2332G>A	p.Ala778Thr	missense	Exon 8 of 8	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 2 AN: 17452 Hom.: 0 Cov.: 0

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000631 AC: 15 AN: 237876 Hom.: 0 Cov.: 5 AF XY: 0.0000544 AC XY: 6 AN XY: 110346

African (AFR) AF: 0.00 AC: 0 AN: 4598

American (AMR) AF: 0.00309 AC: 1 AN: 324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1476

East Asian (EAS) AF: 0.00 AC: 0 AN: 986

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 90

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 452

European-Non Finnish (NFE) AF: 0.0000598 AC: 13 AN: 217358

Other (OTH) AF: 0.000127 AC: 1 AN: 7876

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000115 AC: 2 AN: 17452 Hom.: 0 Cov.: 0 AF XY: 0.000119 AC XY: 1 AN XY: 8406

African (AFR) AF: 0.00 AC: 0 AN: 4434

American (AMR) AF: 0.00 AC: 0 AN: 1476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 392

East Asian (EAS) AF: 0.00 AC: 0 AN: 820

South Asian (SAS) AF: 0.00 AC: 0 AN: 684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 42

European-Non Finnish (NFE) AF: 0.000235 AC: 2 AN: 8512

Other (OTH) AF: 0.00 AC: 0 AN: 214

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.060
Sift	Benign	0.33	T
Sift4G	Benign	0.25	T
Polyphen		0.029	B
Vest4		0.085
MutPred		0.34		Gain of glycosylation at A778 (P = 4e-04)
MVP		0.54
MPC		1.1
ClinPred		0.095	T
GERP RS		1.0
Varity_R		0.029
gMVP		0.52
Mutation Taster		=94/6	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: rs1060499864; hg19: chr19-616136;