5-45266487-A-G

Variant names:

• chr5-45266487-A-G
• rs4866929
• NM_021072.4:c.1783+602T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021072.4(HCN1):​c.1783+602T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 152,054 control chromosomes in the GnomAD database, including 11,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (11141 hom., cov: 32)
• Consequence: HCN1 NM_021072.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.750
• Publications: 11 publications found

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]

HCN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• generalized epilepsy with febrile seizures plus, type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-45266487-A-G is Benign according to our data. Variant chr5-45266487-A-G is described in ClinVar as Benign. ClinVar VariationId is 3256856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.1783+602T>C		intron	N/A	NP_066550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.1783+602T>C		intron	N/A	ENSP00000307342.4
	HCN1	ENST00000673735.1		c.*8+28T>C		intron	N/A	ENSP00000501107.1
	HCN1	ENST00000637305.1	TSL:5	n.946+602T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51986 AN: 151936 Hom.: 11142 Cov.: 32

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.381

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.342 AC: 51986 AN: 152054 Hom.: 11141 Cov.: 32 AF XY: 0.342 AC XY: 25438 AN XY: 74302

African (AFR) AF: 0.0836 AC: 3472 AN: 41522

American (AMR) AF: 0.415 AC: 6339 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1398 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5164

South Asian (SAS) AF: 0.201 AC: 968 AN: 4820

European-Finnish (FIN) AF: 0.550 AC: 5793 AN: 10526

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 31021 AN: 67976

Other (OTH) AF: 0.379 AC: 800 AN: 2110

Alfa AF: 0.428 Hom.: 30650

Bravo AF: 0.326

Asia WGS AF: 0.250 AC: 871 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 68. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.6
DANN	Benign	0.73
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs4866929; hg19: chr5-45266589;