22-36922263-G-A

Variant names:

• chr22-36922263-G-A
• rs777889990
• NM_000395.3:c.56G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000395.3(CSF2RB):​c.56G>A​(p.Arg19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,427,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R19R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CSF2RB NM_000395.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.02

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]

ENSG00000304449 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028493851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF2RB	NM_000395.3	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 14	ENST00000403662.8	NP_000386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF2RB	ENST00000403662.8	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 14	5	NM_000395.3	ENSP00000384053.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000156 AC: 3 AN: 191698 AF XY: 0.0000194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000684

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1427094 Hom.: 0 Cov.: 31 AF XY: 0.00000991 AC XY: 7 AN XY: 706622

African (AFR) AF: 0.0000304 AC: 1 AN: 32898

American (AMR) AF: 0.00 AC: 0 AN: 40032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 38116

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1094930

Other (OTH) AF: 0.0000339 AC: 2 AN: 59002

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000612 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 19 of the CSF2RB protein (p.Arg19His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CSF2RB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2422111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CSF2RB protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.024
DANN	Benign	0.40
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-2.9
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.55	N;.;N
PhyloP100		-2.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.52	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.027
MutPred		0.39		Gain of catalytic residue at L21 (P = 0.0667);Gain of catalytic residue at L21 (P = 0.0667);Gain of catalytic residue at L21 (P = 0.0667);
MVP		0.58
MPC		0.18
ClinPred		0.023	T
GERP RS		-7.8
PromoterAI		-0.0038	Neutral
Varity_R		0.0098
gMVP		0.14
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

Publications

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Other links and lift over

dbSNP: rs777889990; hg19: chr22-37318305;