8-66177084-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000756.4(CRH):ā€‹c.394C>Gā€‹(p.Leu132Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,445,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

CRH
NM_000756.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.044605345).
BS2
High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRHNM_000756.4 linkuse as main transcriptc.394C>G p.Leu132Val missense_variant 2/2 ENST00000276571.5 NP_000747.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRHENST00000276571.5 linkuse as main transcriptc.394C>G p.Leu132Val missense_variant 2/21 NM_000756.4 ENSP00000276571 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000139
AC:
3
AN:
215896
Hom.:
0
AF XY:
0.00000850
AC XY:
1
AN XY:
117628
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000613
Gnomad SAS exome
AF:
0.0000349
Gnomad FIN exome
AF:
0.0000524
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000125
AC:
18
AN:
1445654
Hom.:
0
Cov.:
31
AF XY:
0.0000139
AC XY:
10
AN XY:
717868
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000236
Gnomad4 FIN exome
AF:
0.0000193
Gnomad4 NFE exome
AF:
0.0000136
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.0000167
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.394C>G (p.L132V) alteration is located in exon 2 (coding exon 1) of the CRH gene. This alteration results from a C to G substitution at nucleotide position 394, causing the leucine (L) at amino acid position 132 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
0.065
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
8.3
DANN
Benign
0.85
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.045
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.15
N
REVEL
Benign
0.067
Sift
Benign
0.52
T
Sift4G
Benign
0.65
T
Polyphen
0.012
B
Vest4
0.016
MutPred
0.14
Gain of MoRF binding (P = 0.1323);
MVP
0.17
MPC
1.1
ClinPred
0.020
T
GERP RS
4.4
Varity_R
0.047
gMVP
0.33

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

LitVar

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

Other links and lift over

dbSNP: rs766492442; hg19: chr8-67089319; API