Genetic Variant CRHR2:p.Val240Ile (chr7-30662196-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001883.5(CRHR2):c.718G>A(p.Val240Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,956 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 22 hom., cov: 33)

Exomes 𝑓: 0.011 ( 133 hom. )

Consequence

CRHR2
NM_001883.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.986

Publications

18 publications found

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:

ENSG00000305335 (HGNC:):

ENSG00000305335 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067519546).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2221/152166) while in subpopulation AFR AF = 0.0265 (1100/41514). AF 95% confidence interval is 0.0252. There are 22 homozygotes in GnomAd4. There are 1060 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHR2	NM_001883.5 link	c.718G>A	p.Val240Ile	missense_variant	Exon 7 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.718G>A	p.Val240Ile	missense_variant	Exon 7 of 12	1	NM_001883.5	ENSP00000418722.1		Q13324-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2221

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0118

AC:

2957

AN:

251352

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0106

AC:

15464

AN:

1461790

Hom.:

133

Cov.:

AF XY:

0.0107

AC XY:

7748

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0301

AC:

1008

AN:

33480

American (AMR)

AF:

0.0127

AC:

567

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

447

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0130

AC:

1124

AN:

86248

European-Finnish (FIN)

AF:

0.00313

AC:

167

AN:

53414

Middle Eastern (MID)

AF:

0.0348

AC:

201

AN:

5768

European-Non Finnish (NFE)

AF:

0.00998

AC:

11102

AN:

1111950

Other (OTH)

AF:

0.0140

AC:

846

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

769

1539

2308

3078

3847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

426

852

1278

1704

2130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2221

AN:

152166

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1060

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0265

AC:

1100

AN:

41514

American (AMR)

AF:

0.0141

AC:

215

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0108

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

727

AN:

68006

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0165

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.0129

AC:

1562

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.079

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.048

.;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0068

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;.;N;.

PhyloP100

-0.99

PrimateAI

Benign

0.26

PROVEAN

Benign

0.13

N;N;N;N

REVEL

Benign

0.023

Sift

Benign

0.60

T;T;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0020, 0.0010

.;B;B;B

Vest4

0.13

MPC

0.20

ClinPred

0.00076

GERP RS

1.3

Varity_R

0.097

gMVP

0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over