Genetic Variant CRHBP:p.His164Arg (chr5-76955810-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_001882.4(CRHBP):c.491A>G(p.His164Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CRHBP
NM_001882.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.97

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 5-76955810-A-G is Benign according to our data. Variant chr5-76955810-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3497042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHBP	NM_001882.4 link	c.491A>G	p.His164Arg	missense_variant	Exon 4 of 7	ENST00000274368.9	NP_001873.2	P24387
CRHBP	XM_047416736.1 link	c.305A>G	p.His102Arg	missense_variant	Exon 3 of 6		XP_047272692.1
CRHBP	XR_948235.4 link	n.581A>G		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRHBP	ENST00000274368.9 link	c.491A>G	p.His164Arg	missense_variant	Exon 4 of 7	1	NM_001882.4	ENSP00000274368.4	P24387
CRHBP	ENST00000506501.1 link	c.491A>G	p.His164Arg	missense_variant	Exon 4 of 5	1		ENSP00000426097.1	D6RHH7
CRHBP	ENST00000512446.1 link	n.594A>G		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251478

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 11, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.27

DEOGEN2

Uncertain

0.60

D;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.83

T;T

Sift4G

Uncertain

0.018

D;D

Polyphen

0.76

P;P

Vest4

0.23

MutPred

0.89

Gain of MoRF binding (P = 0.0333);Gain of MoRF binding (P = 0.0333);

MVP

0.43

MPC

0.65

ClinPred

0.33

GERP RS

3.5

Varity_R

0.19

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over