dbSNP rs748404250: CRH:p.Pro30Leu (chr8-66177389-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000756.4(CRH):c.89C>T(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRH
NM_000756.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

5 publications found

Variant links:

Genes affected

CRH (HGNC:2355): (corticotropin releasing hormone) This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition. [provided by RefSeq, Nov 2015]

CRH links:

LINC00967 (HGNC:48725): (long intergenic non-protein coding RNA 967)

LINC00967 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05504015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRH	NM_000756.4 link	c.89C>T	p.Pro30Leu	missense_variant	Exon 2 of 2	ENST00000276571.5	NP_000747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CRH	ENST00000276571.5 link	c.89C>T	p.Pro30Leu	missense_variant	Exon 2 of 2	1	NM_000756.4	ENSP00000276571.3
LINC00967	ENST00000729586.1 link	n.128G>A		non_coding_transcript_exon_variant	Exon 1 of 4
LINC00967	ENST00000729591.1 link	n.152G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1387376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684472

African (AFR)

AF:

0.00

AC:

AN:

31390

American (AMR)

AF:

0.00

AC:

AN:

35768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35722

South Asian (SAS)

AF:

0.00

AC:

AN:

79214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078576

Other (OTH)

AF:

0.00

AC:

AN:

57784

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

M_CAP

Benign

0.040

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

2.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.090

REVEL

Benign

0.037

Sift

Benign

0.11

Sift4G

Benign

0.18

Vest4

0.065

ClinPred

0.26

GERP RS

2.8

Varity_R

0.045

gMVP

0.27

Mutation Taster

=71/29

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over