NM_001883.5:c.1195C>T

Variant names:

• chr7-30653501-G-A
• rs757121565
• NM_001883.5:c.1195C>T

Variant summary

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

The NM_001883.5(CRHR2):​c.1195C>T​(p.Arg399Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CRHR2 NM_001883.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.267
• Publications: 1 publications found

Genes affected

CRHR2 (HGNC:2358): (corticotropin releasing hormone receptor 2) The protein encoded by this gene belongs to the G-protein coupled receptor 2 family, and the subfamily of corticotropin releasing hormone receptor. This receptor shows high affinity for corticotropin releasing hormone (CRH), and also binds CRH-related peptides such as urocortin. CRH is synthesized in the hypothalamus, and plays an important role in coordinating the endocrine, autonomic, and behavioral responses to stress and immune challenge. Studies in mice suggest that this receptor maybe involved in mediating cardiovascular homeostasis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jan 2011]

ENSG00000305335 (HGNC:):

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001883.5. 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
	CRHR2	NM_001883.5	MANE Select	c.1195C>T	p.Arg399Trp	missense	Exon 12 of 12	NP_001874.2
	CRHR2	NM_001202475.1		c.1276C>T	p.Arg426Trp	missense	Exon 13 of 13	NP_001189404.1	Q13324-2
	CRHR2	NM_001202482.2		c.1192C>T	p.Arg398Trp	missense	Exon 12 of 12	NP_001189411.1	Q13324-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRHR2	ENST00000471646.6	TSL:1 MANE Select	c.1195C>T	p.Arg399Trp	missense	Exon 12 of 12	ENSP00000418722.1	Q13324-1
	CRHR2	ENST00000348438.8	TSL:1	c.1276C>T	p.Arg426Trp	missense	Exon 13 of 13	ENSP00000340943.4	Q13324-2
	CRHR2	ENST00000506074.6	TSL:1	c.*142C>T		3_prime_UTR	Exon 13 of 13	ENSP00000426498.3	Q13324-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249276 AF XY: 0.0000371

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461454 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727036

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000404 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.17	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.27
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.49		Loss of disorder (P = 4e-04)
MVP		0.80
MPC		0.91
ClinPred		0.27	T
GERP RS		-1.6
Varity_R		0.26
gMVP		0.77
Mutation Taster		=46/54	disease causing

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: rs757121565; hg19: chr7-30693117;