rs1876828

Variant names:

• chr17-45834159-C-A
• rs1876828
• NM_004382.5:c.1107+111C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-45834159-C-A
• chr17-45834159-C-T

GermlineCancer (beta)

Variant summary

Our verdict is

Likely benign

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -2 classification points (ACMG Germline Pathogenicity v2019): 2P and 4B. PM2BP4_Strong

The NM_004382.5(CRHR1):c.1107+111C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000115, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: CRHR1 NM_004382.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 0 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]

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -2 points.

• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000115 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004382.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRHR1	NM_004382.5	MANE Select	c.1107+111C>A		intron	N/A	NP_004373.2
	CRHR1	NM_001145146.2		c.1194+111C>A		intron	N/A	NP_001138618.1	P34998-1
	CRHR1	NM_001145148.2		c.1065+310C>A		intron	N/A	NP_001138620.1	P34998-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRHR1	ENST00000314537.10	TSL:1 MANE Select	c.1107+111C>A		intron	N/A	ENSP00000326060.6	P34998-2
	CRHR1	ENST00000398285.7	TSL:1	c.1194+111C>A		intron	N/A	ENSP00000381333.3	P34998-1
	CRHR1	ENST00000577353.5	TSL:1	c.1065+310C>A		intron	N/A	ENSP00000462016.1	P34998-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.41e-7 AC: 1 AN: 1188530 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 601394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28756

American (AMR) AF: 0.00 AC: 0 AN: 42828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23144

East Asian (EAS) AF: 0.00 AC: 0 AN: 38584

South Asian (SAS) AF: 0.00 AC: 0 AN: 78848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5128

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 872756

Other (OTH) AF: 0.00 AC: 0 AN: 51344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.56
PhyloP100		-0.26

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1876828;

hg19: chr17-43911525;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar