chr5-45695870-T-TCGC

Position:

• chr5-45695870-T-TCGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The ENST00000303230.6(HCN1):​c.223_224insGCG​(p.Gly74dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000223 in 1,563,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: HCN1 ENST00000303230.6 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000303230.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-45695870-T-TCGC is Benign according to our data. Variant chr5-45695870-T-TCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412769.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000236 (35/148110) while in subpopulation EAS AF= 0.00144 (7/4858). AF 95% confidence interval is 0.000676. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN1	NM_021072.4	c.223_224insGCG	p.Gly74dup	inframe_insertion	1/8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.223_224insGCG	p.Gly74dup	inframe_insertion	1/8	1	NM_021072.4	ENSP00000307342	P2
HCN1	ENST00000634658.1	c.223_224insGCG	p.Gly74dup	inframe_insertion	1/2	3		ENSP00000489134
HCN1	ENST00000673735.1	c.223_224insGCG	p.Gly74dup	inframe_insertion	1/9			ENSP00000501107	A2

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 35 AN: 147992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00144

Gnomad SAS AF: 0.000433

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000270

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 25 AN: 164440 Hom.: 0 AF XY: 0.000215 AC XY: 20 AN XY: 93110

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.0000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.000575

Gnomad FIN exome AF: 0.000171

Gnomad NFE exome AF: 0.0000788

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000221 AC: 313 AN: 1415334 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 160 AN XY: 702528

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.0000765

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.000370

Gnomad4 SAS exome AF: 0.000599

Gnomad4 FIN exome AF: 0.0000730

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.000359

GnomAD4 genome AF: 0.000236 AC: 35 AN: 148110 Hom.: 0 Cov.: 32 AF XY: 0.000263 AC XY: 19 AN XY: 72346

Gnomad4 AFR AF: 0.000174

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00144

Gnomad4 SAS AF: 0.000433

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000270

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 05, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 24, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

HCN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;