Genetic Variant NM_001883.5:c.1231G>A (chr7-30653465-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001883.5(CRHR2):c.1231G>A(p.Val411Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,284 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0090 ( 11 hom., cov: 32)

Exomes 𝑓: 0.013 ( 135 hom. )

Consequence

CRHR2
NM_001883.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.31

Variant links:

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]

CRHR2 links:

LOC124901609 (HGNC:):

LOC124901609 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068634152).

BP6

Variant 7-30653465-C-T is Benign according to our data. Variant chr7-30653465-C-T is described in ClinVar as [Benign]. Clinvar id is 780674.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-30653465-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHR2	NM_001883.5 link	c.1231G>A	p.Val411Met	missense_variant	Exon 12 of 12	ENST00000471646.6	NP_001874.2	Q13324-1A0A090N7T4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHR2	ENST00000471646.6 link	c.1231G>A	p.Val411Met	missense_variant	Exon 12 of 12	1	NM_001883.5	ENSP00000418722.1		Q13324-1

Frequencies

GnomAD3 genomes

AF:

0.00905

AC:

1376

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00877

AC:

2187

AN:

249346

Hom.:

AF XY:

0.00885

AC XY:

1192

AN XY:

134734

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.00999

GnomAD4 exome

AF:

0.0129

AC:

18845

AN:

1461090

Hom.:

135

Cov.:

AF XY:

0.0126

AC XY:

9133

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00584

Gnomad4 ASJ exome

AF:

0.00261

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.0142

Gnomad4 NFE exome

AF:

0.0150

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.00904

AC:

1376

AN:

152194

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

664

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00797

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0154

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00803

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00899

AC:

1092

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

.;T;.

Eigen

Benign

-0.029

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.8

.;L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.66

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.028

D;D;D

Polyphen

0.99

D;D;B

Vest4

0.22

MVP

0.64

MPC

0.38

ClinPred

0.022

GERP RS

3.5

Varity_R

0.067

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over