chr8-66176242-C-A

Variant names:

• chr8-66176242-C-A
• rs6982394
• NM_000756.4:c.*645G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000756.4(CRH):​c.*645G>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 152,160 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (802 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CRH NM_000756.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.333
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontal lobe epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000756.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRH	NM_000756.4	MANE Select	c.*645G>T		downstream_gene	N/A	NP_000747.1	A0A0S2Z478

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRH	ENST00000276571.5	TSL:1 MANE Select	c.*645G>T		downstream_gene	N/A	ENSP00000276571.3	P06850
	CRH	ENST00000948625.1		c.*645G>T		downstream_gene	N/A	ENSP00000618684.1

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12266 AN: 152042 Hom.: 800 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0470

Gnomad OTH AF: 0.0666

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0807 AC: 12276 AN: 152160 Hom.: 802 Cov.: 32 AF XY: 0.0790 AC XY: 5877 AN XY: 74388

African (AFR) AF: 0.176 AC: 7298 AN: 41476

American (AMR) AF: 0.0475 AC: 726 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 147 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4830

European-Finnish (FIN) AF: 0.0605 AC: 640 AN: 10574

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0470 AC: 3194 AN: 68010

Other (OTH) AF: 0.0659 AC: 139 AN: 2110

Alfa AF: 0.0509 Hom.: 129

Bravo AF: 0.0825

Asia WGS AF: 0.0170 AC: 61 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.53
PhyloP100		0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6982394; hg19: chr8-67088477;