22-36930401-G-C

Variant names:

• chr22-36930401-G-C
• rs16845
• NM_000395.3:c.745G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000403662.8(CSF2RB):​c.745G>C​(p.Glu249Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 1,613,500 control chromosomes in the GnomAD database, including 5,117 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1169 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3948 hom.)
• Consequence: CSF2RB ENST00000403662.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.68
• Publications: 23 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: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001964748).
• BP6: Variant 22-36930401-G-C is Benign according to our data. Variant chr22-36930401-G-C is described in ClinVar as Benign. ClinVar VariationId is 226555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000403662.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RB	NM_000395.3	MANE Select	c.745G>C	p.Glu249Gln	missense	Exon 7 of 14	NP_000386.1
	CSF2RB	NM_001410827.1		c.745G>C	p.Glu249Gln	missense	Exon 7 of 14	NP_001397756.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RB	ENST00000403662.8	TSL:5 MANE Select	c.745G>C	p.Glu249Gln	missense	Exon 7 of 14	ENSP00000384053.3
	CSF2RB	ENST00000406230.5	TSL:1	c.745G>C	p.Glu249Gln	missense	Exon 6 of 13	ENSP00000385271.1
	CSF2RB	ENST00000421539.1	TSL:5	c.505G>C	p.Glu169Gln	missense	Exon 6 of 7	ENSP00000393585.1

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14981 AN: 152058 Hom.: 1167 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.0698 AC: 17552 AN: 251354 AF XY: 0.0706

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0551

Gnomad OTH exome AF: 0.0713

GnomAD4 exome AF: 0.0632 AC: 92414 AN: 1461324 Hom.: 3948 Cov.: 34 AF XY: 0.0649 AC XY: 47207 AN XY: 726952

African (AFR) AF: 0.230 AC: 7707 AN: 33470

American (AMR) AF: 0.0393 AC: 1757 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2704 AN: 26134

East Asian (EAS) AF: 0.00290 AC: 115 AN: 39700

South Asian (SAS) AF: 0.133 AC: 11456 AN: 86230

European-Finnish (FIN) AF: 0.0378 AC: 2020 AN: 53390

Middle Eastern (MID) AF: 0.119 AC: 635 AN: 5324

European-Non Finnish (NFE) AF: 0.0556 AC: 61879 AN: 1112004

Other (OTH) AF: 0.0686 AC: 4141 AN: 60348

GnomAD4 genome AF: 0.0986 AC: 15011 AN: 152176 Hom.: 1169 Cov.: 32 AF XY: 0.0973 AC XY: 7242 AN XY: 74402

African (AFR) AF: 0.212 AC: 8795 AN: 41486

American (AMR) AF: 0.0572 AC: 875 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3468

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.151 AC: 728 AN: 4816

European-Finnish (FIN) AF: 0.0333 AC: 354 AN: 10622

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0529 AC: 3600 AN: 67998

Other (OTH) AF: 0.0871 AC: 184 AN: 2112

Alfa AF: 0.0628 Hom.: 311

Bravo AF: 0.103

TwinsUK AF: 0.0604 AC: 224

ALSPAC AF: 0.0607 AC: 234

ESP6500AA AF: 0.212 AC: 934

ESP6500EA AF: 0.0544 AC: 468

ExAC AF: 0.0743 AC: 9018

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0558

EpiControl AF: 0.0609

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.7	N
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.027
MPC		0.15
ClinPred		0.0030	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.32
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16845; hg19: chr22-37326443;