5-45695870-TCGCCGC-T

Variant names:

• chr5-45695870-TCGCCGC-T
• rs747975797
• NM_021072.4:c.218_223delGCGGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_021072.4(HCN1):​c.218_223delGCGGCG​(p.Gly73_Gly74del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00344 in 1,563,414 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• 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: Benign. The variant received -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BP6: Variant 5-45695870-TCGCCGC-T is Benign according to our data. Variant chr5-45695870-TCGCCGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 305 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.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	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.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000307342.4
	HCN1	ENST00000947598.1		c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000501107.1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 305 AN: 147994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000933

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00606

Gnomad FIN AF: 0.000297

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00442

GnomAD2 exomes AF: 0.00343 AC: 564 AN: 164440 AF XY: 0.00369

Gnomad AFR exome AF: 0.000400

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000343

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00359 AC: 5076 AN: 1415302 Hom.: 18 AF XY: 0.00369 AC XY: 2595 AN XY: 702502

African (AFR) AF: 0.000636 AC: 20 AN: 31432

American (AMR) AF: 0.00145 AC: 57 AN: 39234

Ashkenazi Jewish (ASJ) AF: 0.000481 AC: 12 AN: 24940

East Asian (EAS) AF: 0.00 AC: 0 AN: 37856

South Asian (SAS) AF: 0.00728 AC: 596 AN: 81868

European-Finnish (FIN) AF: 0.000633 AC: 26 AN: 41106

Middle Eastern (MID) AF: 0.000378 AC: 2 AN: 5298

European-Non Finnish (NFE) AF: 0.00385 AC: 4214 AN: 1095072

Other (OTH) AF: 0.00255 AC: 149 AN: 58496

GnomAD4 genome AF: 0.00206 AC: 305 AN: 148112 Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 142 AN XY: 72348

African (AFR) AF: 0.000372 AC: 15 AN: 40302

American (AMR) AF: 0.000932 AC: 14 AN: 15028

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4858

South Asian (SAS) AF: 0.00606 AC: 28 AN: 4618

European-Finnish (FIN) AF: 0.000297 AC: 3 AN: 10108

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

European-Non Finnish (NFE) AF: 0.00353 AC: 235 AN: 66570

Other (OTH) AF: 0.00437 AC: 9 AN: 2058

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00210

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	HCN1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=185/15	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; COSMIC: COSV57541955; COSMIC: COSV57541955;