rs1060500096

chr5-45696026-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_021072.4(HCN1):c.68C>T(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,322,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26

Genes affected

HCN1 (HGNC:4845): (hyperpolarization activated cyclic nucleotide gated potassium channel 1) The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1497806).
• BP6: Variant 5-45696026-G-A is Benign according to our data. Variant chr5-45696026-G-A is described in ClinVar as [Benign]. Clinvar id is 404097.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000534 (8/149764) while in subpopulation AMR AF= 0.000332 (5/15072). AF 95% confidence interval is 0.00013. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.68C>T	p.Ala23Val	missense_variant	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.68C>T	p.Ala23Val	missense_variant	1/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.68C>T	p.Ala23Val	missense_variant	1/9			A2
HCN1	ENST00000634658.1	c.68C>T	p.Ala23Val	missense_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0000535 AC: 8 AN: 149658 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000571 AC: 4 AN: 70014 Hom.: 0 AF XY: 0.0000732 AC XY: 3 AN XY: 40962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.000162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 15 AN: 1172872 Hom.: 0 Cov.: 32 AF XY: 0.0000122 AC XY: 7 AN XY: 574866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.000330

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.000110

GnomAD4 genome AF: 0.0000534 AC: 8 AN: 149764 Hom.: 0 Cov.: 32 AF XY: 0.0000684 AC XY: 5 AN XY: 73066

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000332

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000298

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.23
Sift	Benign	0.17	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.0	B;.
Vest4		0.068
MVP		0.32
MPC		2.1
ClinPred		0.049	T
GERP RS		-1.2
Varity_R		0.039
gMVP		0.098

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: rs1060500096; hg19: chr5-45696128;