8-66177406-C-T

Position:

• chr8-66177406-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000756.4(CRH):​c.72G>A​(p.Ala24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,539,610 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: CRH NM_000756.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.136

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-66177406-C-T is Benign according to our data. Variant chr8-66177406-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 587969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.136 with no splicing effect.
• BS2: High AC in GnomAd4 at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRH	NM_000756.4	c.72G>A	p.Ala24=	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	c.72G>A	p.Ala24=	synonymous_variant	2/2	1	NM_000756.4	ENSP00000276571	P1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000510 AC: 68 AN: 133460 Hom.: 0 AF XY: 0.000411 AC XY: 30 AN XY: 73052

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.000654

Gnomad ASJ exome AF: 0.000622

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000397

Gnomad OTH exome AF: 0.000741

GnomAD4 exome AF: 0.000401 AC: 557 AN: 1387338 Hom.: 2 Cov.: 32 AF XY: 0.000380 AC XY: 260 AN XY: 684610

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.000952

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.0000522

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.000969

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74442

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000492 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2016

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.5
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs560106713; hg19: chr8-67089641;