17-45830530-T-C

Variant names:

• chr17-45830530-T-C
• rs16940665
• NM_004382.5:c.669T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004382.5(CRHR1):​c.669T>C​(p.Thr223Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,992 control chromosomes in the GnomAD database, including 32,770 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 (2139 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30631 hom.)
• Consequence: CRHR1 NM_004382.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.10
• Publications: 70 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.802652).
• BP7: Synonymous conserved (PhyloP=-5.1 with no splicing effect.
• 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.669T>C	p.Thr223Thr	synonymous_variant	Exon 7 of 13	ENST00000314537.10	NP_004373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10	c.669T>C	p.Thr223Thr	synonymous_variant	Exon 7 of 13	1	NM_004382.5	ENSP00000326060.6
LINC02210-CRHR1	ENST00000634540.1	c.144T>C	p.Thr48Thr	synonymous_variant	Exon 9 of 15	2		ENSP00000488912.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21838 AN: 152150 Hom.: 2141 Cov.: 33

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.145 AC: 36154 AN: 248984 AF XY: 0.149

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000668

Gnomad FIN exome AF: 0.0676

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.193 AC: 282562 AN: 1460724 Hom.: 30631 Cov.: 34 AF XY: 0.191 AC XY: 138799 AN XY: 726634

African (AFR) AF: 0.0366 AC: 1226 AN: 33468

American (AMR) AF: 0.125 AC: 5596 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6715 AN: 26076

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39692

South Asian (SAS) AF: 0.0795 AC: 6850 AN: 86200

European-Finnish (FIN) AF: 0.0720 AC: 3813 AN: 52934

Middle Eastern (MID) AF: 0.202 AC: 1161 AN: 5760

European-Non Finnish (NFE) AF: 0.222 AC: 246482 AN: 1111592

Other (OTH) AF: 0.177 AC: 10684 AN: 60356

GnomAD4 genome AF: 0.143 AC: 21828 AN: 152268 Hom.: 2139 Cov.: 33 AF XY: 0.134 AC XY: 9994 AN XY: 74458

African (AFR) AF: 0.0430 AC: 1786 AN: 41568

American (AMR) AF: 0.176 AC: 2689 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0739 AC: 357 AN: 4828

European-Finnish (FIN) AF: 0.0648 AC: 688 AN: 10624

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

European-Non Finnish (NFE) AF: 0.217 AC: 14761 AN: 67980

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.200 Hom.: 5846

Bravo AF: 0.148

TwinsUK AF: 0.234 AC: 867

ALSPAC AF: 0.241 AC: 930

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.224 AC: 1925

ExAC AF: 0.144 AC: 17510

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
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.7
DANN	Benign	0.54
FATHMM_MKL	Benign	0.020	N
PhyloP100		-5.1
Vest4		0.70
GERP RS		-4.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16940665; hg19: chr17-43907896;