rs16940674

Variant names:

• chr17-45833141-C-T
• rs16940674
• NM_004382.5:c.774C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004382.5(CRHR1):​c.774C>T​(p.Cys258Cys) variant causes a synonymous change. The variant allele was found at a frequency of 0.188 in 1,611,846 control chromosomes in the GnomAD database, including 32,679 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 0.14 (2135 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30544 hom.)
• Consequence: CRHR1 NM_004382.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• Publications: 42 publications found

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: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]

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHR1	NM_004382.5	c.774C>T	p.Cys258Cys	synonymous_variant	Exon 9 of 13	ENST00000314537.10	NP_004373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10	c.774C>T	p.Cys258Cys	synonymous_variant	Exon 9 of 13	1	NM_004382.5	ENSP00000326060.6
LINC02210-CRHR1	ENST00000634540.1	c.249C>T	p.Cys83Cys	synonymous_variant	Exon 11 of 15	2		ENSP00000488912.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21803 AN: 152106 Hom.: 2137 Cov.: 33

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.145 AC: 36277 AN: 249506 AF XY: 0.149

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.000667

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.193 AC: 281417 AN: 1459622 Hom.: 30544 Cov.: 36 AF XY: 0.190 AC XY: 138306 AN XY: 726240

African (AFR) AF: 0.0365 AC: 1222 AN: 33478

American (AMR) AF: 0.125 AC: 5610 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6580 AN: 26120

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39700

South Asian (SAS) AF: 0.0796 AC: 6861 AN: 86240

European-Finnish (FIN) AF: 0.0722 AC: 3857 AN: 53398

Middle Eastern (MID) AF: 0.201 AC: 1158 AN: 5762

European-Non Finnish (NFE) AF: 0.221 AC: 245455 AN: 1109878

Other (OTH) AF: 0.176 AC: 10639 AN: 60328

GnomAD4 genome AF: 0.143 AC: 21793 AN: 152224 Hom.: 2135 Cov.: 33 AF XY: 0.134 AC XY: 9981 AN XY: 74440

African (AFR) AF: 0.0429 AC: 1783 AN: 41560

American (AMR) AF: 0.176 AC: 2690 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3462

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5166

South Asian (SAS) AF: 0.0741 AC: 357 AN: 4818

European-Finnish (FIN) AF: 0.0648 AC: 688 AN: 10616

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14754 AN: 67996

Other (OTH) AF: 0.182 AC: 385 AN: 2110

Alfa AF: 0.188 Hom.: 3263

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		5.0
PromoterAI		0.013	Neutral
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16940674; hg19: chr17-43910507;