7-30662196-C-T

Position:

• chr7-30662196-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000471646.6(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 33)
  • Exomes 𝑓: 0.011 (133 hom.)
• Consequence: CRHR2 ENST00000471646.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.986

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067519546).
• BP6: Variant 7-30662196-C-T is Benign according to our data. Variant chr7-30662196-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRHR2	NM_001883.5	c.718G>A	p.Val240Ile	missense_variant	7/12	ENST00000471646.6	NP_001874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRHR2	ENST00000471646.6	c.718G>A	p.Val240Ile	missense_variant	7/12	1	NM_001883.5	ENSP00000418722	P1

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

GnomAD3 exomes AF: 0.0118 AC: 2957 AN: 251352 Hom.: 36 AF XY: 0.0117 AC XY: 1588 AN XY: 135860

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 SAS exome AF: 0.0129

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

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00998

Gnomad4 OTH exome AF: 0.0140

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

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0123 Hom.: 26

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 v4.3

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;D;D;D
MetaRNN	Benign	0.0068	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.;N;.
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.26	T
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	T
GERP RS		1.3
Varity_R		0.097
gMVP		0.21

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

LitVar

Other links and lift over

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