22-36937894-C-T

Variant names:

• chr22-36937894-C-T
• rs16997517
• NM_000395.3:c.2086C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 22 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=0.0019168258).
• BP6: Variant 22-36937894-C-T is Benign according to our data. Variant chr22-36937894-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000395.3. 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.2086C>T	p.Pro696Ser	missense	Exon 14 of 14	NP_000386.1
	CSF2RB	NM_001410827.1		c.2104C>T	p.Pro702Ser	missense	Exon 14 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.2086C>T	p.Pro696Ser	missense	Exon 14 of 14	ENSP00000384053.3
	CSF2RB	ENST00000406230.5	TSL:1	c.2104C>T	p.Pro702Ser	missense	Exon 13 of 13	ENSP00000385271.1

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

GnomAD2 exomes AF: 0.0265 AC: 6656 AN: 251332 AF XY: 0.0266

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 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

African (AFR) AF: 0.122 AC: 4095 AN: 33480

American (AMR) AF: 0.0158 AC: 705 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 332 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0526 AC: 4540 AN: 86258

European-Finnish (FIN) AF: 0.00565 AC: 302 AN: 53412

Middle Eastern (MID) AF: 0.0406 AC: 234 AN: 5768

European-Non Finnish (NFE) AF: 0.0201 AC: 22300 AN: 1111988

Other (OTH) AF: 0.0255 AC: 1541 AN: 60396

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

African (AFR) AF: 0.111 AC: 4628 AN: 41538

American (AMR) AF: 0.0276 AC: 422 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0631 AC: 304 AN: 4818

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1313 AN: 67998

Other (OTH) AF: 0.0389 AC: 82 AN: 2108

Alfa AF: 0.0266 Hom.: 292

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

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	0.078
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.1
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.74
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.21
Sift	Benign	0.067	T
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.011
MPC		0.22
ClinPred		0.067	T
GERP RS		-1.1
Varity_R		0.046
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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