rs6159

Positions:

chr8-66177190-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000756.4(CRH):c.288A>C(p.Gly96=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,540,854 control chromosomes in the GnomAD database, including 41,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 12446 hom., cov: 33)

Exomes 𝑓: 0.18 ( 28876 hom. )

Consequence

CRH
NM_000756.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.425

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 8-66177190-T-G is Benign according to our data. Variant chr8-66177190-T-G is described in ClinVar as [Benign]. Clinvar id is 585725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.425 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRH	NM_000756.4 linkuse as main transcript	c.288A>C	p.Gly96=	synonymous_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.288A>C	p.Gly96=	synonymous_variant	2/2	1	NM_000756.4	ENSP00000276571	P1

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49721

AN:

152096

Hom.:

12403

Cov.:

show subpopulations

Gnomad AFR

AF:

0.693

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.276

GnomAD3 exomes

AF:

0.227

AC:

32232

AN:

141894

Hom.:

4964

AF XY:

0.213

AC XY:

16370

AN XY:

76840

show subpopulations

Gnomad AFR exome

AF:

0.703

Gnomad AMR exome

AF:

0.339

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.326

Gnomad SAS exome

AF:

0.176

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.180

AC:

250096

AN:

1388640

Hom.:

28876

Cov.:

AF XY:

0.177

AC XY:

121393

AN XY:

685414

show subpopulations

Gnomad4 AFR exome

AF:

0.701

Gnomad4 AMR exome

AF:

0.342

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.363

Gnomad4 SAS exome

AF:

0.175

Gnomad4 FIN exome

AF:

0.136

Gnomad4 NFE exome

AF:

0.156

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.327

AC:

49825

AN:

152214

Hom.:

12446

Cov.:

AF XY:

0.325

AC XY:

24168

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.693

Gnomad4 AMR

AF:

0.334

Gnomad4 ASJ

AF:

0.122

Gnomad4 EAS

AF:

0.338

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.156

Gnomad4 OTH

AF:

0.283

Alfa

AF:

0.200

Hom.:

1428

Bravo

AF:

0.355

Asia WGS

AF:

0.287

AC:

999

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.3

DANN

Benign

0.73

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