chr22-36937930-GC-G

Variant names:

• chr22-36937930-GC-G
• rs568607741
• NM_000395.3:c.2124delC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_000395.3(CSF2RB):​c.2124delC​(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
• Publications: 2 publications found

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]

CSF2RB Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 5

  Inheritance: AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.212 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• 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 VariationId is 402566.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000395.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RB	NM_000395.3	MANE Select	c.2124delC	p.Ser709LeufsTer22	frameshift	Exon 14 of 14	NP_000386.1	P32927-1
	CSF2RB	NM_001410827.1		c.2142delC	p.Ser715LeufsTer22	frameshift	Exon 14 of 14	NP_001397756.1	P32927-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RB	ENST00000403662.8	TSL:5 MANE Select	c.2124delC	p.Ser709LeufsTer22	frameshift	Exon 14 of 14	ENSP00000384053.3	P32927-1
	CSF2RB	ENST00000406230.5	TSL:1	c.2142delC	p.Ser715LeufsTer22	frameshift	Exon 13 of 13	ENSP00000385271.1	P32927-2
	CSF2RB	ENST00000910856.1		c.2160delC	p.Ser721LeufsTer22	frameshift	Exon 14 of 14	ENSP00000580915.1

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

GnomAD2 exomes AF: 0.00183 AC: 461 AN: 251406 AF XY: 0.00178

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 592 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000918 AC: 49 AN: 53404

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000739 AC: 822 AN: 1112006

Other (OTH) AF: 0.00247 AC: 149 AN: 60396

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

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 67996

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00407 Hom.: 0

Bravo AF: 0.00117

EpiCase AF: 0.00109

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=30/170	disease causing (ClinVar)

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: rs568607741; hg19: chr22-37333972; COSMIC: COSV53258103;