5-45695870-TCGCCGCCGCCGCCGCCGCCGC-TCGC

Variant names:

• chr5-45695870-TCGCCGCCGCCGCCGCCGC-T
• rs747975797
• NM_021072.4:c.206_223delGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM4 BP6_Moderate

The NM_021072.4(HCN1):​c.206_223delGCGGCGGCGGCGGCGGCG​(p.Gly69_Gly74del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000128 in 1,563,354 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.52
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BP6: Variant 5-45695870-TCGCCGCCGCCGCCGCCGC-T is Benign according to our data. Variant chr5-45695870-TCGCCGCCGCCGCCGCCGC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3725296.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.206_223delGCGGCGGCGGCGGCGGCG	p.Gly69_Gly74del	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.206_223delGCGGCGGCGGCGGCGGCG	p.Gly69_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.206_223delGCGGCGGCGGCGGCGGCG	p.Gly69_Gly74del	disruptive_inframe_deletion	Exon 1 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.206_223delGCGGCGGCGGCGGCGGCG	p.Gly69_Gly74del	disruptive_inframe_deletion	Exon 1 of 2	3		ENSP00000489134.1
HCN1	ENST00000638054.1	n.-163_-146delGCGGCGGCGGCGGCGGCG		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 702546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31432

American (AMR) AF: 0.00 AC: 0 AN: 39240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24940

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37864

South Asian (SAS) AF: 0.00 AC: 0 AN: 81870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095108

Other (OTH) AF: 0.00 AC: 0 AN: 58500

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 147994 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72228

African (AFR) AF: 0.00 AC: 0 AN: 40186

American (AMR) AF: 0.00 AC: 0 AN: 15008

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4872

South Asian (SAS) AF: 0.00 AC: 0 AN: 4618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66580

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=187/13	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs747975797; hg19: chr5-45695972;