Genetic Variant HCRT:c.21+16T>C (chr17-42185329-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001524.1(HCRT):c.21+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,613,018 control chromosomes in the GnomAD database, including 7,654 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 4031 hom., cov: 32)

Exomes 𝑓: 0.014 ( 3623 hom. )

Consequence

HCRT
NM_001524.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.657

Publications

9 publications found

Variant links:

Genes affected

HCRT (HGNC:4847): (hypocretin neuropeptide precursor) This gene encodes a hypothalamic neuropeptide precursor protein that gives rise to two mature neuropeptides, orexin A and orexin B, by proteolytic processing. Orexin A and orexin B, which bind to orphan G-protein coupled receptors HCRTR1 and HCRTR2, function in the regulation of sleep and arousal. This neuropeptide arrangement may also play a role in feeding behavior, metabolism, and homeostasis. [provided by RefSeq, Jan 2010]

HCRT Gene-Disease associations (from GenCC):

narcolepsy 1
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

HCRT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001524.1. 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
	HCRT	NM_001524.1	MANE Select	c.21+16T>C		intron	N/A	NP_001515.1	O43612

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRT	ENST00000293330.1	TSL:1 MANE Select	c.21+16T>C		intron	N/A	ENSP00000293330.1	O43612

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19038

AN:

151882

Hom.:

4000

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0445

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0209

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.0876

GnomAD2 exomes

AF:

0.0344

AC:

8643

AN:

251340

AF XY:

0.0259

show subpopulations

Gnomad AFR exome

AF:

0.446

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0140

AC:

20523

AN:

1461018

Hom.:

3623

Cov.:

AF XY:

0.0124

AC XY:

9041

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.450

AC:

15021

AN:

33402

American (AMR)

AF:

0.0229

AC:

1025

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26126

East Asian (EAS)

AF:

0.0345

AC:

1371

AN:

39694

South Asian (SAS)

AF:

0.00479

AC:

413

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.0258

AC:

149

AN:

5768

European-Non Finnish (NFE)

AF:

0.000603

AC:

670

AN:

1111286

Other (OTH)

AF:

0.0307

AC:

1853

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

664

1328

1991

2655

3319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.126

AC:

19119

AN:

152000

Hom.:

4031

Cov.:

AF XY:

0.122

AC XY:

9077

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.435

AC:

18016

AN:

41402

American (AMR)

AF:

0.0444

AC:

679

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.0209

AC:

108

AN:

5164

South Asian (SAS)

AF:

0.00664

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

67970

Other (OTH)

AF:

0.0867

AC:

183

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

540

1080

1621

2161

2701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0500

Hom.:

3943

Bravo

AF:

0.143

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.25

(source)

DANN

Benign

0.36

PhyloP100

-0.66

PromoterAI

0.074

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over