chr22-36922263-G-A

Position:

• chr22-36922263-G-A

Variant summary

Our verdict is Likely benign. Variant got -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. 16/21 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]

LOC105373023 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
CSF2RB	NM_000395.3	c.56G>A	p.Arg19His	missense_variant	2/14	ENST00000403662.8
LOC105373023	XR_938230.2	n.195-3324C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RB	ENST00000403662.8	c.56G>A	p.Arg19His	missense_variant	2/14	5	NM_000395.3	P1
CSF2RB	ENST00000406230.5	c.56G>A	p.Arg19His	missense_variant	1/13	1

Frequencies

GnomAD3 genomes Cov.: 33

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

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000836 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2023

This variant has not been reported in the literature in individuals affected with CSF2RB-related conditions. 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. 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. 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 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). -

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
MutationTaster	Benign	1.0	N;N;N
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
Varity_R		0.0098
gMVP		0.14

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: rs777889990; hg19: chr22-37318305;