rs12936511

Positions:

• chr17-45807036-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001303020.2(CRHR1):​c.-158C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 1,613,946 control chromosomes in the GnomAD database, including 1,257 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (73 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1184 hom.)
• Consequence: CRHR1 NM_001303020.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.28

Genes affected

LINC02210-CRHR1 (HGNC:51483): (LINC02210-CRHR1 readthrough) This locus represents naturally occurring readthrough transcription between neighboring genes CRHR1-IT1, CRHR1 intronic transcript 1 (Gene ID: 147081) and CRHR1, corticotropin releasing hormone receptor 1 (Gene ID: 1394) on chromosome 17. The readthrough transcript encodes a protein that shares sequence identity with the product of the CRHR1 gene. [provided by RefSeq, Dec 2016]

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]

CRHR1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0297 (4526/152290) while in subpopulation NFE AF= 0.0437 (2970/68018). AF 95% confidence interval is 0.0424. There are 73 homozygotes in gnomad4. There are 2143 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4526 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRHR1	NM_004382.5	c.60C>T	p.Pro20Pro	synonymous_variant	2/13	ENST00000314537.10	NP_004373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LINC02210-CRHR1	ENST00000634540.1	c.-466C>T		5_prime_UTR_premature_start_codon_gain_variant	4/15	2		ENSP00000488912.1
CRHR1	ENST00000314537.10	c.60C>T	p.Pro20Pro	synonymous_variant	2/13	1	NM_004382.5	ENSP00000326060.6
LINC02210-CRHR1	ENST00000634540.1	c.-466C>T		5_prime_UTR_variant	4/15	2		ENSP00000488912.1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4521 AN: 152172 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.00989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0311 AC: 7752 AN: 249060 Hom.: 152 AF XY: 0.0319 AC XY: 4307 AN XY: 135120

Gnomad AFR exome AF: 0.00852

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0456

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0389 AC: 56908 AN: 1461656 Hom.: 1184 Cov.: 31 AF XY: 0.0384 AC XY: 27946 AN XY: 727132

Gnomad4 AFR exome AF: 0.00771

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0138

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0436

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0297 AC: 4526 AN: 152290 Hom.: 73 Cov.: 33 AF XY: 0.0288 AC XY: 2143 AN XY: 74456

Gnomad4 AFR AF: 0.00989

Gnomad4 AMR AF: 0.0259

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0404

Gnomad4 NFE AF: 0.0437

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0379 Hom.: 51

Bravo AF: 0.0281

Asia WGS AF: 0.0300 AC: 105 AN: 3476

EpiCase AF: 0.0419

EpiControl AF: 0.0425

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.2
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12936511; hg19: chr17-43884402;