rs16845

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000395.3(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.099 (1169 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3948 hom.)
• Consequence: CSF2RB NM_000395.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.68

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF2RB	NM_000395.3	c.745G>C	p.Glu249Gln	missense_variant	Exon 7 of 14	ENST00000403662.8	NP_000386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF2RB	ENST00000403662.8	c.745G>C	p.Glu249Gln	missense_variant	Exon 7 of 14	5	NM_000395.3	ENSP00000384053.3
CSF2RB	ENST00000406230.5	c.745G>C	p.Glu249Gln	missense_variant	Exon 6 of 13	1		ENSP00000385271.1
CSF2RB	ENST00000421539.1	c.505G>C	p.Glu169Gln	missense_variant	Exon 6 of 7	5		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

GnomAD3 exomes AF: 0.0698 AC: 17552 AN: 251354 Hom.: 974 AF XY: 0.0706 AC XY: 9587 AN XY: 135882

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 SAS exome AF: 0.136

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

Gnomad4 AFR exome AF: 0.230

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.00290

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0378

Gnomad4 NFE exome AF: 0.0556

Gnomad4 OTH exome AF: 0.0686

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

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.0954

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0871

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu249Gln in exon 7 of CSF2RB: This variant is not expected to have clinical sig nificance because it has been identified in 21.2% (934/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs16845). -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.32	T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.7	N;.;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.1	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.027
MPC		0.15
ClinPred		0.0030	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs16845; hg19: chr22-37326443;