NM_021072.4:c.201_209delTGGCGGCGG

Variant names:

• chr5-45695884-GCCGCCGCCA-G
• rs56064803
• NM_021072.4:c.201_209delTGGCGGCGG

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_021072.4(HCN1):​c.201_209delTGGCGGCGG​(p.Gly68_Gly70del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,529,748 control chromosomes in the GnomAD database, including 621 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G67G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (87 hom., cov: 32)
  • Exomes 𝑓: 0.020 (534 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.38
• Publications: 3 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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4.
• BP6: Variant 5-45695884-GCCGCCGCCA-G is Benign according to our data. Variant chr5-45695884-GCCGCCGCCA-G is described in ClinVar as Benign. ClinVar VariationId is 95999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

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.201_209delTGGCGGCGG	p.Gly68_Gly70del	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.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000307342.4
	HCN1	ENST00000947598.1		c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000501107.1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4277 AN: 150482 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000398

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00774

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0222

GnomAD2 exomes AF: 0.0198 AC: 2842 AN: 143504 AF XY: 0.0205

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.000429

Gnomad FIN exome AF: 0.00688

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0204 AC: 28203 AN: 1379162 Hom.: 534 AF XY: 0.0205 AC XY: 14004 AN XY: 681950

African (AFR) AF: 0.0643 AC: 1981 AN: 30824

American (AMR) AF: 0.0132 AC: 442 AN: 33594

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 38 AN: 24366

East Asian (EAS) AF: 0.000165 AC: 6 AN: 36266

South Asian (SAS) AF: 0.0289 AC: 2283 AN: 78892

European-Finnish (FIN) AF: 0.00701 AC: 266 AN: 37968

Middle Eastern (MID) AF: 0.0288 AC: 147 AN: 5102

European-Non Finnish (NFE) AF: 0.0203 AC: 21842 AN: 1074886

Other (OTH) AF: 0.0209 AC: 1198 AN: 57264

GnomAD4 genome AF: 0.0284 AC: 4280 AN: 150586 Hom.: 87 Cov.: 32 AF XY: 0.0264 AC XY: 1942 AN XY: 73588

African (AFR) AF: 0.0619 AC: 2548 AN: 41156

American (AMR) AF: 0.0166 AC: 251 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3462

East Asian (EAS) AF: 0.000399 AC: 2 AN: 5010

South Asian (SAS) AF: 0.0216 AC: 103 AN: 4772

European-Finnish (FIN) AF: 0.00774 AC: 80 AN: 10332

Middle Eastern (MID) AF: 0.0313 AC: 9 AN: 288

European-Non Finnish (NFE) AF: 0.0181 AC: 1222 AN: 67402

Other (OTH) AF: 0.0219 AC: 46 AN: 2096

Alfa AF: 0.00609 Hom.: 5

Asia WGS AF: 0.0110 AC: 36 AN: 3400

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=190/10	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs56064803; hg19: chr5-45695986; COSMIC: COSV57500386; COSMIC: COSV57500386;