rs56154381

Variant names:

• chr5-45267081-T-TA
• rs56154381
• NM_021072.4:c.1783+7dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021072.4(HCN1):​c.1783+7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,607,762 control chromosomes in the GnomAD database, including 862 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (448 hom., cov: 31)
  • Exomes 𝑓: 0.0098 (414 hom.)
• Consequence: HCN1 NM_021072.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.222
• 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 -16 ACMG points.

• BP6: Variant 5-45267081-T-TA is Benign according to our data. Variant chr5-45267081-T-TA is described in ClinVar as Benign. ClinVar VariationId is 198584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.1783+7dupT		splice_region intron	N/A	NP_066550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.1783+7_1783+8insT		splice_region intron	N/A	ENSP00000307342.4
	HCN1	ENST00000673735.1		c.1783+7_1783+8insT		splice_region intron	N/A	ENSP00000501107.1
	HCN1	ENST00000637305.1	TSL:5	n.946+7_946+8insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6991 AN: 152060 Hom.: 441 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00812

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0162 AC: 4074 AN: 251488 AF XY: 0.0136

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00982 AC: 14299 AN: 1455584 Hom.: 414 Cov.: 28 AF XY: 0.00954 AC XY: 6912 AN XY: 724692

African (AFR) AF: 0.145 AC: 4829 AN: 33324

American (AMR) AF: 0.0124 AC: 553 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00889 AC: 232 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00654 AC: 563 AN: 86128

European-Finnish (FIN) AF: 0.00270 AC: 144 AN: 53404

Middle Eastern (MID) AF: 0.0269 AC: 155 AN: 5756

European-Non Finnish (NFE) AF: 0.00624 AC: 6907 AN: 1106332

Other (OTH) AF: 0.0152 AC: 915 AN: 60190

GnomAD4 genome AF: 0.0462 AC: 7030 AN: 152178 Hom.: 448 Cov.: 31 AF XY: 0.0452 AC XY: 3365 AN XY: 74414

African (AFR) AF: 0.144 AC: 5989 AN: 41484

American (AMR) AF: 0.0196 AC: 300 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.00812 AC: 552 AN: 67998

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0222 Hom.: 34

Bravo AF: 0.0520

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00984

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs56154381; hg19: chr5-45267183;