rs568607741

chr22-36937930-GC-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000395.3(CSF2RB):c.2124del(p.Ser709LeufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,138 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: CSF2RB NM_000395.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.281

Genes affected

CSF2RB (HGNC:2436): (colony stimulating factor 2 receptor subunit beta) The protein encoded by this gene is the common beta chain of the high affinity receptor for IL-3, IL-5 and CSF. Defects in this gene have been reported to be associated with protein alveolar proteinosis (PAP). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 22-36937930-GC-G is Benign according to our data. Variant chr22-36937930-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402566.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RB	NM_000395.3	c.2124del	p.Ser709LeufsTer22	frameshift_variant	14/14	ENST00000403662.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RB	ENST00000403662.8	c.2124del	p.Ser709LeufsTer22	frameshift_variant	14/14	5	NM_000395.3	P1
CSF2RB	ENST00000406230.5	c.2142del	p.Ser715LeufsTer22	frameshift_variant	13/13	1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00183 AC: 461 AN: 251406 Hom.: 2 AF XY: 0.00178 AC XY: 242 AN XY: 135888

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00113 AC: 1653 AN: 1461870 Hom.: 9 Cov.: 35 AF XY: 0.00114 AC XY: 830 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00407 Hom.: 0

Bravo AF: 0.00117

EpiCase AF: 0.00109

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Variant proposed as a risk allele for Crohn's disease in the Ashkenazi Jewish population (Chuang et al., 2016; Levine et al., 2016); Published functional studies suggest a damaging effect, as intestinal monocytes from carriers of this variant had reduced responses to granulocyte-macrophage colony-stimulating factor (Chuang et al., 2016); Frameshift variant predicted to result in protein truncation as the last 189 amino acids are lost and replaced with 21 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27377463, 34426522, 27373512, 34662886) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 05, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with Pulmonary alveolar proteinosis, but frequency is too high for disorder, and this is a frameshift in the last exon. Limited evidence for gene-disease association. One LOF variant has been reported, but frequency of this variant is too high for pathogenic role in this disease. -

Computational scores

Source: dbNSFP v4.3

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: rs568607741; hg19: chr22-37333972;