chr8-66177022-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000756.4(CRH):c.456G>A(p.Arg152Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,034 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 21 hom. )

Consequence

CRH
NM_000756.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.09

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 8-66177022-C-T is Benign according to our data. Variant chr8-66177022-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.09 with no splicing effect.

BS2

High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRH	NM_000756.4 link	c.456G>A	p.Arg152Arg	synonymous_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.456G>A	p.Arg152Arg	synonymous_variant	Exon 2 of 2	1	NM_000756.4	ENSP00000276571.3
LINC00967	ENST00000729586.1 link	n.-240C>T		upstream_gene_variant
LINC00967	ENST00000729591.1 link	n.-216C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00314

AC:

788

AN:

250622

AF XY:

0.00402

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00225

AC:

3284

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

1943

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33462

American (AMR)

AF:

0.00134

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00494

AC:

129

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0131

AC:

1130

AN:

86206

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00157

AC:

1747

AN:

1111938

Other (OTH)

AF:

0.00262

AC:

158

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

204

408

613

817

1021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152358

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41588

American (AMR)

AF:

0.00124

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00766

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00188

AC:

128

AN:

68040

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00191

Hom.:

Bravo

AF:

0.00144

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 24, 2016

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. -

CRH-related disorder

Benign:1

Oct 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

2.1

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over