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17-45829614-C-A

Variant summary

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

The ENST00000398285.7(CRHR1):c.488C>A(p.Ala163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,551,054 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A163S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00026 ( 6 hom. )

Consequence

CRHR1
ENST00000398285.7 missense

Scores

1
13

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.67
Variant links:
Genes affected
CRHR1 (HGNC:2357): (corticotropin releasing hormone receptor 1) This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]
MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

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=0.010003358).
BP6
Variant 17-45829614-C-A is Benign according to our data. Variant chr17-45829614-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3034597.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRHR1NM_004382.5 linkuse as main transcriptc.434+293C>A intron_variant ENST00000314537.10
LINC02210-CRHR1NM_001256299.3 linkuse as main transcriptc.-92+293C>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRHR1ENST00000314537.10 linkuse as main transcriptc.434+293C>A intron_variant 1 NM_004382.5 P1P34998-2
MAPT-AS1ENST00000634876.2 linkuse as main transcriptn.604-253G>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152134
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00331
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000670
AC:
103
AN:
153740
Hom.:
2
AF XY:
0.000968
AC XY:
79
AN XY:
81640
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00448
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000231
GnomAD4 exome
AF:
0.000264
AC:
369
AN:
1398802
Hom.:
6
Cov.:
32
AF XY:
0.000378
AC XY:
261
AN XY:
689926
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00448
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.000172
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.000202
AC XY:
15
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00332
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.00151
AC:
39
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

CRHR1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 28, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.43
Cadd
Benign
3.3
Dann
Benign
0.85
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.49
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.31
T
Sift4G
Uncertain
0.025
D;D
Polyphen
0.17
.;B
Vest4
0.14
MutPred
0.60
Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);
MVP
0.75
MPC
1.6
ClinPred
0.030
T
GERP RS
-0.40
Varity_R
0.073
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs576726381; hg19: chr17-43906980; API