5-76953174-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001882.4(CRHBP):c.40A>G(p.Ile14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CRHBP
NM_001882.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.130

Publications

0 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:

S100Z (HGNC:30367): (S100 calcium binding protein Z) Members of the S100 protein family contain 2 calcium-binding EF-hands and exhibit cell-type specific expression patterns. For additional background information on S100 proteins, see MIM 114085.[supplied by OMIM, Mar 2008]

S100Z links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09154785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHBP	NM_001882.4 link	c.40A>G	p.Ile14Val	missense_variant	Exon 1 of 7	ENST00000274368.9	NP_001873.2	P24387
CRHBP	XR_948235.4 link	n.130A>G		non_coding_transcript_exon_variant	Exon 1 of 8
S100Z	XM_011543241.3 link	c.*342A>G		downstream_gene_variant			XP_011541543.1	Q8WXG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRHBP	ENST00000274368.9 link	c.40A>G	p.Ile14Val	missense_variant	Exon 1 of 7	1	NM_001882.4	ENSP00000274368.4	P24387
CRHBP	ENST00000506501.1 link	c.40A>G	p.Ile14Val	missense_variant	Exon 1 of 5	1		ENSP00000426097.1	D6RHH7
CRHBP	ENST00000512446.1 link	n.-243A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459388

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726030

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109912

Other (OTH)

AF:

0.00

AC:

AN:

60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40A>G (p.I14V) alteration is located in exon 1 (coding exon 1) of the CRHBP gene. This alteration results from a A to G substitution at nucleotide position 40, causing the isoleucine (I) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.092

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

L;.

PhyloP100

0.13

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.35

N;N

REVEL

Benign

0.063

Sift

Benign

0.52

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.041

B;B

Vest4

0.11

MutPred

0.56

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.11

MPC

0.46

ClinPred

0.22

GERP RS

-1.1

PromoterAI

0.031

Neutral

(source)

Varity_R

0.028

gMVP

0.33

Mutation Taster

=93/7

polymorphism

(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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5-76953174-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over