chr5-76958851-G-C

Variant names:

• chr5-76958851-G-C
• rs1745730821
• NM_001882.4:c.655G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001882.4(CRHBP):​c.655G>C​(p.Asp219His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRHBP NM_001882.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHBP	NM_001882.4	c.655G>C	p.Asp219His	missense_variant	Exon 5 of 7	ENST00000274368.9	NP_001873.2
CRHBP	XM_047416736.1	c.469G>C	p.Asp157His	missense_variant	Exon 4 of 6		XP_047272692.1
CRHBP	XR_948235.4	n.745G>C		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHBP	ENST00000274368.9	c.655G>C	p.Asp219His	missense_variant	Exon 5 of 7	1	NM_001882.4	ENSP00000274368.4
CRHBP	ENST00000506501.1	c.655G>C	p.Asp219His	missense_variant	Exon 5 of 5	1		ENSP00000426097.1
CRHBP	ENST00000514258.1	n.155G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3
CRHBP	ENST00000512446.1	n.*7G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.655G>C (p.D219H) alteration is located in exon 5 (coding exon 5) of the CRHBP gene. This alteration results from a G to C substitution at nucleotide position 655, causing the aspartic acid (D) at amino acid position 219 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		7.7
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.053	T;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.83	P;D
Vest4		0.53
MutPred		0.71		Gain of methylation at K216 (P = 0.0736);Gain of methylation at K216 (P = 0.0736);
MVP		0.26
MPC		1.5
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.48
Mutation Taster		=79/21	polymorphism

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: rs1745730821; hg19: chr5-76254676;