8-66177389-G-C

Position:

chr8-66177389-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000756.4(CRH):c.89C>G(p.Pro30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,539,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CRH
NM_000756.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 2.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004918188).

BP6

Variant 8-66177389-G-C is Benign according to our data. Variant chr8-66177389-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 183027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRH	NM_000756.4 linkuse as main transcript	c.89C>G	p.Pro30Arg	missense_variant	2/2	ENST00000276571.5	NP_000747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRH	ENST00000276571.5 linkuse as main transcript	c.89C>G	p.Pro30Arg	missense_variant	2/2	1	NM_000756.4	ENSP00000276571	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

134428

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

73640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

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:

0.000314

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

AF:

0.000226

AC:

314

AN:

1387374

Hom.:

Cov.:

AF XY:

0.000218

AC XY:

149

AN XY:

684470

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.000275

Gnomad4 OTH exome

AF:

0.000225

GnomAD4 genome

AF:

0.000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000273

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000119

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 11, 2013	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2017

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. -

Autosomal dominant nocturnal frontal lobe epilepsy

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.42

REVEL

Benign

0.14

Sift

Benign

0.043

Sift4G

Benign

0.10

Polyphen

0.092

Vest4

0.16

MutPred

0.20

Gain of methylation at P30 (P = 0.0127);

MVP

0.68

MPC

2.2

ClinPred

0.065

GERP RS

2.8

Varity_R

0.046

gMVP

0.31

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.

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