chr5-45695870-TCGCCGCCGCCGC-T

Variant names:

• chr5-45695870-TCGCCGCCGCCGC-T
• rs747975797
• NM_021072.4:c.212_223delGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_021072.4(HCN1):​c.212_223delGCGGCGGCGGCG​(p.Gly71_Gly74del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000012 in 1,415,348 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52
• Publications: 0 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: Orphanet, ClinGen
• 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: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.212_223delGCGGCGGCGGCG	p.Gly71_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	NP_066550.2	O60741

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.212_223delGCGGCGGCGGCG	p.Gly71_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000307342.4	O60741
	HCN1	ENST00000947598.1		c.212_223delGCGGCGGCGGCG	p.Gly71_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.212_223delGCGGCGGCGGCG	p.Gly71_Gly74del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000501107.1	A0A669KB45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1415348 Hom.: 0 AF XY: 0.0000128 AC XY: 9 AN XY: 702544

African (AFR) AF: 0.00 AC: 0 AN: 31430

American (AMR) AF: 0.00 AC: 0 AN: 39236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24938

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000155 AC: 17 AN: 1095104

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

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;