chr5-45695870-T-TCGCCGC

Position:

• chr5-45695870-T-TCGCCGC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

The NM_021072.4(HCN1):​c.223_224insGCGGCG​(p.Gly73_Gly74dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000108 in 1,563,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: HCN1 NM_021072.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.52

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000122 (18/148112) while in subpopulation SAS AF= 0.00065 (3/4618). AF 95% confidence interval is 0.000176. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/8	1	NM_021072.4	P2
HCN1	ENST00000634658.1	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/2	3
HCN1	ENST00000673735.1	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/9			A2

Frequencies

GnomAD3 genomes AF: 0.000122 AC: 18 AN: 147994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.000650

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.000492

GnomAD4 exome AF: 0.000107 AC: 151 AN: 1415348 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 76 AN XY: 702536

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.0000765

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000185

Gnomad4 SAS exome AF: 0.000195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000986

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.000122 AC: 18 AN: 148112 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 9 AN XY: 72348

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.000333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000206

Gnomad4 SAS AF: 0.000650

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.000486

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2023	In-frame duplication of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

This variant, c.218_223dup, results in the insertion of 2 amino acid(s) of the HCN1 protein (p.Gly73_Gly74dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCN1-related conditions. This variant has been observed in at least one individual who was not affected with HCN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 647637). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs747975797; hg19: chr5-45695972;