dbSNP rs41272246: CRHBP:c.81+22C>A (chr5-76953237-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001882.4(CRHBP):c.81+22C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,607,350 control chromosomes in the GnomAD database, including 1,234 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 0.037 ( 100 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1134 hom. )

Consequence

CRHBP
NM_001882.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.148

Publications

3 publications found

Variant links:

Genes affected

CRHBP (HGNC:2356): (corticotropin releasing hormone binding protein) Corticotropin-releasing hormone is a potent stimulator of synthesis and secretion of preopiomelanocortin-derived peptides. Although CRH concentrations in the human peripheral circulation are normally low, they increase throughout pregnancy and fall rapidly after parturition. Maternal plasma CRH probably originates from the placenta. Human plasma contains a CRH-binding protein which inactivates CRH and which may prevent inappropriate pituitary-adrenal stimulation in pregnancy. [provided by RefSeq, Jul 2008]

CRHBP links:

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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=-0.73).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0365 (5562/152316) while in subpopulation NFE AF = 0.0411 (2795/68018). AF 95% confidence interval is 0.0398. There are 100 homozygotes in GnomAd4. There are 2636 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 100 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHBP	NM_001882.4 link	c.81+22C>A		intron_variant	Intron 1 of 6	ENST00000274368.9	NP_001873.2	P24387
CRHBP	XR_948235.4 link	n.171+22C>A		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRHBP	ENST00000274368.9 link	c.81+22C>A	intron_variant	Intron 1 of 6	1	NM_001882.4	ENSP00000274368.4	P24387
CRHBP	ENST00000506501.1 link	c.81+22C>A	intron_variant	Intron 1 of 4	1		ENSP00000426097.1	D6RHH7
CRHBP	ENST00000512446.1 link	n.-180C>A	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0365

AC:

5558

AN:

152198

Hom.:

100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0317

Gnomad AMI

AF:

0.0659

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0248

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0425

GnomAD2 exomes

AF:

0.0344

AC:

8522

AN:

247972

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.0333

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0677

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0428

Gnomad NFE exome

AF:

0.0424

Gnomad OTH exome

AF:

0.0388

GnomAD4 exome

AF:

0.0388

AC:

56490

AN:

1455034

Hom.:

1134

Cov.:

AF XY:

0.0385

AC XY:

27867

AN XY:

724310

show subpopulations

African (AFR)

AF:

0.0325

AC:

1084

AN:

33304

American (AMR)

AF:

0.0226

AC:

1008

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0638

AC:

1663

AN:

26068

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39668

South Asian (SAS)

AF:

0.0248

AC:

2135

AN:

86052

European-Finnish (FIN)

AF:

0.0448

AC:

2390

AN:

53388

Middle Eastern (MID)

AF:

0.0505

AC:

291

AN:

5758

European-Non Finnish (NFE)

AF:

0.0413

AC:

45637

AN:

1105934

Other (OTH)

AF:

0.0379

AC:

2279

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2855

5711

8566

11422

14277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1724

3448

5172

6896

8620

<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:

0.0365

AC:

5562

AN:

152316

Hom.:

100

Cov.:

AF XY:

0.0354

AC XY:

2636

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0317

AC:

1317

AN:

41576

American (AMR)

AF:

0.0347

AC:

531

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0248

AC:

120

AN:

4832

European-Finnish (FIN)

AF:

0.0388

AC:

412

AN:

10622

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0411

AC:

2795

AN:

68018

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

267

535

802

1070

1337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0371

Hom.:

Bravo

AF:

0.0358

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.7

(source)

DANN

Benign

0.77

PhyloP100

0.15

PromoterAI

-0.026

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over