22-36921991-C-T

Variant names:

• chr22-36921991-C-T
• rs41280009
• NM_000395.3:c.-172-45C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000395.3(CSF2RB):​c.-172-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 598,760 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (119 hom., cov: 33)
  • Exomes 𝑓: 0.041 (479 hom.)
• Consequence: CSF2RB NM_000395.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304449 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36921991-C-T is Benign according to our data. Variant chr22-36921991-C-T is described in ClinVar as Benign. ClinVar VariationId is 1283425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4841/152292) while in subpopulation NFE AF = 0.0484 (3292/68008). AF 95% confidence interval is 0.047. There are 119 homozygotes in GnomAd4. There are 2289 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 119 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.-172-45C>T		intron	N/A	NP_000386.1	P32927-1
	CSF2RB	NM_001410827.1		c.-172-45C>T		intron	N/A	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.-172-45C>T		intron	N/A	ENSP00000384053.3	P32927-1
	CSF2RB	ENST00000910856.1		c.-172-45C>T		intron	N/A	ENSP00000580915.1
	CSF2RB	ENST00000910857.1		c.-172-45C>T		intron	N/A	ENSP00000580916.1

Frequencies

GnomAD3 genomes AF: 0.0318 AC: 4844 AN: 152174 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0413 AC: 18461 AN: 446468 Hom.: 479 Cov.: 3 AF XY: 0.0421 AC XY: 9868 AN XY: 234246

African (AFR) AF: 0.00800 AC: 101 AN: 12620

American (AMR) AF: 0.0230 AC: 466 AN: 20274

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 378 AN: 13714

East Asian (EAS) AF: 0.000130 AC: 4 AN: 30860

South Asian (SAS) AF: 0.0478 AC: 2234 AN: 46694

European-Finnish (FIN) AF: 0.0348 AC: 1027 AN: 29484

Middle Eastern (MID) AF: 0.0475 AC: 93 AN: 1958

European-Non Finnish (NFE) AF: 0.0496 AC: 13144 AN: 265014

Other (OTH) AF: 0.0392 AC: 1014 AN: 25850

GnomAD4 genome AF: 0.0318 AC: 4841 AN: 152292 Hom.: 119 Cov.: 33 AF XY: 0.0307 AC XY: 2289 AN XY: 74458

African (AFR) AF: 0.00871 AC: 362 AN: 41556

American (AMR) AF: 0.0214 AC: 328 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4828

European-Finnish (FIN) AF: 0.0338 AC: 359 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0484 AC: 3292 AN: 68008

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0464 Hom.: 26

Bravo AF: 0.0301

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.42
DANN	Benign	0.54
PhyloP100		-1.1
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism

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: rs41280009; hg19: chr22-37318033;