chr17-45816520-C-T

Position:

• chr17-45816520-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004382.5(CRHR1):​c.179C>T​(p.Ala60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00795 in 1,614,102 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (73 hom.)
• Consequence: CRHR1 NM_004382.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37

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]

LINC02210-CRHR1 (HGNC:):

MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012295485).
• BP6: Variant 17-45816520-C-T is Benign according to our data. Variant chr17-45816520-C-T is described in ClinVar as [Benign]. Clinvar id is 771768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRHR1	NM_004382.5	c.179C>T	p.Ala60Val	missense_variant	3/13	ENST00000314537.10	NP_004373.2
LINC02210-CRHR1	NM_001256299.3	c.-347C>T		5_prime_UTR_variant	5/15		NP_001243228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10	c.179C>T	p.Ala60Val	missense_variant	3/13	1	NM_004382.5	ENSP00000326060	P1
MAPT-AS1	ENST00000634876.2	n.2593+9063G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152176 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00644 AC: 1603 AN: 248836 Hom.: 11 AF XY: 0.00625 AC XY: 845 AN XY: 135254

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00810 AC: 11841 AN: 1461808 Hom.: 73 Cov.: 32 AF XY: 0.00805 AC XY: 5853 AN XY: 727198

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.00976

Gnomad4 OTH exome AF: 0.00661

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152294 Hom.: 7 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74472

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00621

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00807 Hom.: 3

Bravo AF: 0.00549

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00182 AC: 7

ESP6500EA AF: 0.0108 AC: 89

ExAC AF: 0.00716 AC: 865

EpiCase AF: 0.00851

EpiControl AF: 0.00919

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.30	.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	.;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.051	.;T;.;T
Sift4G	Uncertain	0.058	T;T;T;D
Polyphen		0.12, 0.24, 0.29	.;B;B;B
Vest4		0.15
MVP		0.57
MPC		0.64
ClinPred		0.012	T
GERP RS		4.1
Varity_R		0.55
gMVP		0.81

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: rs16940655; hg19: chr17-43893886;