rs16997517

Positions:

• chr22-36937894-C-T

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.2086C>T​(p.Pro696Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,614,106 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.045 (303 hom., cov: 32)
  • Exomes 𝑓: 0.023 (748 hom.)
• Consequence: CSF2RB NM_000395.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.742

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=0.0019168258).
• BP6: Variant 22-36937894-C-T is Benign according to our data. Variant chr22-36937894-C-T is described in ClinVar as [Benign]. Clinvar id is 226551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF2RB	NM_000395.3	c.2086C>T	p.Pro696Ser	missense_variant	14/14	ENST00000403662.8	NP_000386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF2RB	ENST00000403662.8	c.2086C>T	p.Pro696Ser	missense_variant	14/14	5	NM_000395.3	ENSP00000384053	P1
CSF2RB	ENST00000406230.5	c.2104C>T	p.Pro702Ser	missense_variant	13/13	1		ENSP00000385271

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6873 AN: 152132 Hom.: 300 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0628

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0265 AC: 6656 AN: 251332 Hom.: 199 AF XY: 0.0266 AC XY: 3615 AN XY: 135856

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0543

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0233 AC: 34058 AN: 1461856 Hom.: 748 Cov.: 35 AF XY: 0.0239 AC XY: 17371 AN XY: 727224

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0526

Gnomad4 FIN exome AF: 0.00565

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0453 AC: 6892 AN: 152250 Hom.: 303 Cov.: 32 AF XY: 0.0438 AC XY: 3263 AN XY: 74448

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0631

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0193

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0267 Hom.: 141

Bravo AF: 0.0485

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.114 AC: 504

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0291 AC: 3536

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0235

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Pro696Ser in exon 14 of CSF2RB: This variant is not expected to have clinical si gnificance because it has been identified in 11.4% (504/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16997517). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.1
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.44	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D;.;D
REVEL	Benign	0.21
Sift	Benign	0.067	T;.;T
Sift4G	Benign	0.076	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.011
MPC		0.22
ClinPred		0.067	T
GERP RS		-1.1
Varity_R		0.046
gMVP		0.23

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: rs16997517; hg19: chr22-37333936; COSMIC: COSV53256641;