chr5-45695884-GCCGCCGCCA-G

Variant names:

• chr5-45695884-GCCGCCGCCA-G
• rs56064803
• NM_021072.4:c.201_209delTGGCGGCGG

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_021072.4(HCN1):​c.201_209delTGGCGGCGG​(p.Gly68_Gly70del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,529,748 control chromosomes in the GnomAD database, including 621 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (87 hom., cov: 32)
  • Exomes 𝑓: 0.020 (534 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.38

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BP6: Variant 5-45695884-GCCGCCGCCA-G is Benign according to our data. Variant chr5-45695884-GCCGCCGCCA-G is described in ClinVar as [Benign]. Clinvar id is 95999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45695884-GCCGCCGCCA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 2	3		ENSP00000489134.1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4277 AN: 150482 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000398

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00774

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0222

GnomAD3 exomes AF: 0.0198 AC: 2842 AN: 143504 Hom.: 140 AF XY: 0.0205 AC XY: 1633 AN XY: 79598

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.000429

Gnomad SAS exome AF: 0.0323

Gnomad FIN exome AF: 0.00688

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0204 AC: 28203 AN: 1379162 Hom.: 534 AF XY: 0.0205 AC XY: 14004 AN XY: 681950

Gnomad4 AFR exome AF: 0.0643

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00156

Gnomad4 EAS exome AF: 0.000165

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.00701

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0284 AC: 4280 AN: 150586 Hom.: 87 Cov.: 32 AF XY: 0.0264 AC XY: 1942 AN XY: 73588

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000399

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.00774

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0219

Alfa AF: 0.00609 Hom.: 5

Asia WGS AF: 0.0110 AC: 36 AN: 3400

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 02, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 13, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56064803; hg19: chr5-45695986;