8-66177190-T-G

Variant names:

• chr8-66177190-T-G
• rs6159
• NM_000756.4:c.288A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000756.4(CRH):​c.288A>C​(p.Gly96Gly) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.425
• Publications: 18 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]

LINC00967 (HGNC:48725): (long intergenic non-protein coding RNA 967)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.288A>C	p.Gly96Gly	synonymous	Exon 2 of 2	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.288A>C	p.Gly96Gly	synonymous	Exon 2 of 2	ENSP00000276571.3	P06850
	CRH	ENST00000948625.1		c.288A>C	p.Gly96Gly	synonymous	Exon 2 of 2	ENSP00000618684.1
	LINC00967	ENST00000729586.1		n.-72T>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49721 AN: 152096 Hom.: 12403 Cov.: 33

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

GnomAD2 exomes AF: 0.227 AC: 32232 AN: 141894 AF XY: 0.213

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 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.: 33 AF XY: 0.177 AC XY: 121393 AN XY: 685414

African (AFR) AF: 0.701 AC: 21995 AN: 31360

American (AMR) AF: 0.342 AC: 12193 AN: 35632

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3020 AN: 25124

East Asian (EAS) AF: 0.363 AC: 12962 AN: 35702

South Asian (SAS) AF: 0.175 AC: 13933 AN: 79464

European-Finnish (FIN) AF: 0.136 AC: 5332 AN: 39282

Middle Eastern (MID) AF: 0.165 AC: 914 AN: 5532

European-Non Finnish (NFE) AF: 0.156 AC: 167964 AN: 1078696

Other (OTH) AF: 0.204 AC: 11783 AN: 57848

GnomAD4 genome AF: 0.327 AC: 49825 AN: 152214 Hom.: 12446 Cov.: 33 AF XY: 0.325 AC XY: 24168 AN XY: 74436

African (AFR) AF: 0.693 AC: 28764 AN: 41518

American (AMR) AF: 0.334 AC: 5116 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 425 AN: 3470

East Asian (EAS) AF: 0.338 AC: 1748 AN: 5178

South Asian (SAS) AF: 0.184 AC: 888 AN: 4826

European-Finnish (FIN) AF: 0.144 AC: 1530 AN: 10606

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10640 AN: 68002

Other (OTH) AF: 0.283 AC: 597 AN: 2110

Alfa AF: 0.200 Hom.: 1428

Bravo AF: 0.355

Asia WGS AF: 0.287 AC: 999 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.73
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6159; hg19: chr8-67089425; COSMIC: COSV52541913; COSMIC: COSV52541913;