rs148932124

Variant names:

• chr5-45262797-T-C
• rs148932124
• NM_021072.4:c.1797A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021072.4(HCN1):​c.1797A>G​(p.Ser599Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,613,884 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (30 hom.)
• Consequence: HCN1 NM_021072.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.96
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-45262797-T-C is Benign according to our data. Variant chr5-45262797-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BS2: High AC in GnomAd4 at 611 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.1797A>G	p.Ser599Ser	synonymous	Exon 8 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.1797A>G	p.Ser599Ser	synonymous	Exon 8 of 8	ENSP00000307342.4
	HCN1	ENST00000947598.1		c.1794A>G	p.Ser598Ser	synonymous	Exon 8 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.*22A>G		3_prime_UTR	Exon 9 of 9	ENSP00000501107.1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 611 AN: 152092 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00390 AC: 973 AN: 249266 AF XY: 0.00370

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00488 AC: 7126 AN: 1461674 Hom.: 30 Cov.: 32 AF XY: 0.00469 AC XY: 3408 AN XY: 727126

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00237 AC: 106 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00620 AC: 162 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86250

European-Finnish (FIN) AF: 0.00798 AC: 426 AN: 53396

Middle Eastern (MID) AF: 0.00178 AC: 10 AN: 5610

European-Non Finnish (NFE) AF: 0.00550 AC: 6118 AN: 1112008

Other (OTH) AF: 0.00404 AC: 244 AN: 60374

GnomAD4 genome AF: 0.00401 AC: 611 AN: 152210 Hom.: 4 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74412

African (AFR) AF: 0.000963 AC: 40 AN: 41540

American (AMR) AF: 0.00373 AC: 57 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00792 AC: 84 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00587 AC: 399 AN: 68018

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00520 Hom.: 2

Bravo AF: 0.00350

EpiCase AF: 0.00583

EpiControl AF: 0.00557

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Benign	0.58
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism

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: rs148932124; hg19: chr5-45262899;