5-76954093-C-G

Variant names:

• chr5-76954093-C-G
• NM_001882.4:c.240C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001882.4(CRHBP):​c.240C>G​(p.His80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRHBP NM_001882.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963

Genes affected

CRHBP (HGNC:2356): (corticotropin releasing hormone binding protein) Corticotropin-releasing hormone is a potent stimulator of synthesis and secretion of preopiomelanocortin-derived peptides. Although CRH concentrations in the human peripheral circulation are normally low, they increase throughout pregnancy and fall rapidly after parturition. Maternal plasma CRH probably originates from the placenta. Human plasma contains a CRH-binding protein which inactivates CRH and which may prevent inappropriate pituitary-adrenal stimulation in pregnancy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36461264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHBP	NM_001882.4	c.240C>G	p.His80Gln	missense_variant	Exon 3 of 7	ENST00000274368.9	NP_001873.2
CRHBP	XM_047416736.1	c.54C>G	p.His18Gln	missense_variant	Exon 2 of 6		XP_047272692.1
CRHBP	XR_948235.4	n.330C>G		non_coding_transcript_exon_variant	Exon 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHBP	ENST00000274368.9	c.240C>G	p.His80Gln	missense_variant	Exon 3 of 7	1	NM_001882.4	ENSP00000274368.4
CRHBP	ENST00000506501.1	c.240C>G	p.His80Gln	missense_variant	Exon 3 of 5	1		ENSP00000426097.1
CRHBP	ENST00000512446.1	n.343C>G		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.240C>G (p.H80Q) alteration is located in exon 3 (coding exon 3) of the CRHBP gene. This alteration results from a C to G substitution at nucleotide position 240, causing the histidine (H) at amino acid position 80 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.060
Sift	Benign	0.51	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0070	B;B
Vest4		0.30
MutPred		0.75		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.19
MPC		0.54
ClinPred		0.47	T
GERP RS		2.0
Varity_R		0.093
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-76249918;