5-45695870-TCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr5-45695870-T-TCGC
• rs747975797
• NM_021072.4:c.221_223dupGCG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_021072.4(HCN1):​c.221_223dupGCG​(p.Gly74dup) variant causes a conservative 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 NM_021072.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4. 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 VariationId is 412769.
• BS2: High AC in GnomAd4 at 35 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.221_223dupGCG	p.Gly74dup	conservative_inframe_insertion	Exon 1 of 8	NP_066550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.221_223dupGCG	p.Gly74dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000307342.4
	HCN1	ENST00000947598.1		c.221_223dupGCG	p.Gly74dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.221_223dupGCG	p.Gly74dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000501107.1

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

GnomAD2 exomes AF: 0.000152 AC: 25 AN: 164440 AF XY: 0.000215

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 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

African (AFR) AF: 0.000159 AC: 5 AN: 31432

American (AMR) AF: 0.0000765 AC: 3 AN: 39238

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24938

East Asian (EAS) AF: 0.000370 AC: 14 AN: 37864

South Asian (SAS) AF: 0.000599 AC: 49 AN: 81866

European-Finnish (FIN) AF: 0.0000730 AC: 3 AN: 41108

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

European-Non Finnish (NFE) AF: 0.000198 AC: 217 AN: 1095090

Other (OTH) AF: 0.000359 AC: 21 AN: 58500

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

African (AFR) AF: 0.000174 AC: 7 AN: 40302

American (AMR) AF: 0.0000665 AC: 1 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00144 AC: 7 AN: 4858

South Asian (SAS) AF: 0.000433 AC: 2 AN: 4618

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.000270 AC: 18 AN: 66568

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.0000366 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	HCN1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=75/25	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;