chr7-30662196-C-T

Variant names:

• chr7-30662196-C-T
• rs8192498
• NM_001883.5:c.718G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.986
• Publications: 18 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: 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

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.718G>A	p.Val240Ile	missense	Exon 7 of 12	NP_001874.2
	CRHR2	NM_001202475.1		c.799G>A	p.Val267Ile	missense	Exon 8 of 13	NP_001189404.1	Q13324-2
	CRHR2	NM_001202482.2		c.715G>A	p.Val239Ile	missense	Exon 7 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.718G>A	p.Val240Ile	missense	Exon 7 of 12	ENSP00000418722.1	Q13324-1
	CRHR2	ENST00000348438.8	TSL:1	c.799G>A	p.Val267Ile	missense	Exon 8 of 13	ENSP00000340943.4	Q13324-2
	CRHR2	ENST00000506074.6	TSL:1	c.718G>A	p.Val240Ile	missense	Exon 7 of 13	ENSP00000426498.3	Q13324-4

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2221 AN: 152048 Hom.: 21 Cov.: 33

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

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.: 31 AF XY: 0.0107 AC XY: 7748 AN XY: 727200

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: 2 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

GnomAD4 genome AF: 0.0146 AC: 2221 AN: 152166 Hom.: 22 Cov.: 33 AF XY: 0.0143 AC XY: 1060 AN XY: 74384

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: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4816

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10580

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 727 AN: 68006

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0131 Hom.: 47

Bravo AF: 0.0165

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.0129 AC: 1562

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.079
DANN	Benign	0.38
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.039	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.023
Sift	Benign	0.60	T
Sift4G	Benign	0.63	T
Polyphen		0.0020	B
Vest4		0.13
MPC		0.20
ClinPred		0.00076	T
GERP RS		1.3
Varity_R		0.097
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs8192498; hg19: chr7-30701812; COSMIC: COSV59267330;