4-41745882-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003924.4(PHOX2B):c.870C>A(p.Pro290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,608,784 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P290P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.031 ( 133 hom., cov: 32)

Exomes 𝑓: 0.023 ( 510 hom. )

Consequence

PHOX2B
NM_003924.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.05

Publications

9 publications found

Variant links:

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

PHOX2B Gene-Disease associations (from GenCC):

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Haddad syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
neuroblastoma, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
congenital central hypoventilation syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 4-41745882-G-T is Benign according to our data. Variant chr4-41745882-G-T is described in ClinVar as Benign. ClinVar VariationId is 164943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.870C>A	p.Pro290Pro	synonymous_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 link	c.870C>A	p.Pro290Pro	synonymous_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2 link	n.*151C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0314

AC:

4766

AN:

151750

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0563

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0294

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0393

GnomAD2 exomes

AF:

0.0231

AC:

5584

AN:

241942

AF XY:

0.0219

show subpopulations

Gnomad AFR exome

AF:

0.0559

Gnomad AMR exome

AF:

0.0275

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0262

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0226

GnomAD4 exome

AF:

0.0233

AC:

33934

AN:

1456926

Hom.:

510

Cov.:

AF XY:

0.0228

AC XY:

16557

AN XY:

724804

show subpopulations

African (AFR)

AF:

0.0561

AC:

1846

AN:

32930

American (AMR)

AF:

0.0280

AC:

1245

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

461

AN:

25958

East Asian (EAS)

AF:

0.000102

AC:

AN:

39244

South Asian (SAS)

AF:

0.0175

AC:

1502

AN:

85752

European-Finnish (FIN)

AF:

0.0268

AC:

1421

AN:

52940

Middle Eastern (MID)

AF:

0.00974

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0233

AC:

25868

AN:

1109790

Other (OTH)

AF:

0.0254

AC:

1531

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1793

3586

5378

7171

8964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1002

2004

3006

4008

5010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0314

AC:

4773

AN:

151858

Hom.:

133

Cov.:

AF XY:

0.0305

AC XY:

2264

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.0564

AC:

2339

AN:

41488

American (AMR)

AF:

0.0294

AC:

449

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5138

South Asian (SAS)

AF:

0.0189

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0252

AC:

264

AN:

10480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0219

AC:

1490

AN:

67882

Other (OTH)

AF:

0.0389

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

230

461

691

922

1152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0294

Hom.:

Bravo

AF:

0.0337

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro290Pro in exon 3 of PHOX2B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and has been identi fied in 5.6% (246/4406) of African American chromosomes by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs17885864). -

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

May 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PHOX2B c.870C>A (p.Pro290Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools calculating no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2837/114102 (52 homozygotes, 1/40, frequency: 0.0248637), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PHOX2B variant of 1/1250000 (frequenc: 0.0000008), suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Neuroblastoma, susceptibility to, 2

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Haddad syndrome

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 23, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital central hypoventilation

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.8

(source)

DANN

Benign

0.93

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over