chr7-30653465-C-T

Position:

• chr7-30653465-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000471646.6(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 ENST00000471646.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.31

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]

LOC124901609 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CRHR2	NM_001883.5	c.1231G>A	p.Val411Met	missense_variant	12/12	ENST00000471646.6	NP_001874.2
LOC124901609	XR_007060276.1	n.522-853C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRHR2	ENST00000471646.6	c.1231G>A	p.Val411Met	missense_variant	12/12	1	NM_001883.5	ENSP00000418722	P1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1376 AN: 152076 Hom.: 11 Cov.: 32

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.: 16 AF XY: 0.00885 AC XY: 1192 AN XY: 134734

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.: 31 AF XY: 0.0126 AC XY: 9133 AN XY: 726836

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.: 11 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74402

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.: 12

Bravo AF: 0.00803

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00899 AC: 1092

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	.;T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs77113016; hg19: chr7-30693081;