rs775006915

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003924.4(PHOX2B):c.741_755delCGCGGCAGCGGCGGC(p.Ala248_Ala252del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,204,798 control chromosomes in the GnomAD database, including 44 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 43 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.963

Publications

2 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

BP6

Variant 4-41745996-CGCCGCCGCTGCCGCG-C is Benign according to our data. Variant chr4-41745996-CGCCGCCGCTGCCGCG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0033 (484/146620) while in subpopulation NFE AF = 0.00563 (372/66120). AF 95% confidence interval is 0.00515. There are 1 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 484 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.741_755delCGCGGCAGCGGCGGC	p.Ala248_Ala252del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000226382.4	NP_003915.2	Q99453

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 link	c.741_755delCGCGGCAGCGGCGGC	p.Ala248_Ala252del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.22_36delCGCGGCAGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

484

AN:

146522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000862

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000423

Gnomad FIN

AF:

0.00397

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00563

Gnomad OTH

AF:

0.00348

GnomAD2 exomes

AF:

0.00324

AC:

AN:

12966

AF XY:

0.00285

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00396

Gnomad NFE exome

AF:

0.00493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00494

AC:

5228

AN:

1058178

Hom.:

AF XY:

0.00491

AC XY:

2485

AN XY:

505948

show subpopulations

African (AFR)

AF:

0.000430

AC:

AN:

20944

American (AMR)

AF:

0.000960

AC:

AN:

7292

Ashkenazi Jewish (ASJ)

AF:

0.0000799

AC:

AN:

12514

East Asian (EAS)

AF:

0.00

AC:

AN:

20858

South Asian (SAS)

AF:

0.000957

AC:

AN:

20908

European-Finnish (FIN)

AF:

0.00572

AC:

144

AN:

25156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2800

European-Non Finnish (NFE)

AF:

0.00543

AC:

4928

AN:

906846

Other (OTH)

AF:

0.00291

AC:

119

AN:

40860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

254

508

762

1016

1270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00330

AC:

484

AN:

146620

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

238

AN XY:

71322

show subpopulations

African (AFR)

AF:

0.000860

AC:

AN:

40714

American (AMR)

AF:

0.00221

AC:

AN:

14462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4934

South Asian (SAS)

AF:

0.000423

AC:

AN:

4730

European-Finnish (FIN)

AF:

0.00397

AC:

AN:

9058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00563

AC:

372

AN:

66120

Other (OTH)

AF:

0.00344

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00337

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Aug 11, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PHOX2B c.741_755del15 (p.Ala256_Ala260del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. This variant is located to a poly-alanine repeat region, where the major allele contains a 20 alanine stretch, and this variant removes 5 alanines. The variant allele was found at a frequency of 0.0033 in 145318 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4000-fold of the estimated maximal expected allele frequency for a pathogenic variant in PHOX2B causing Neuroblastoma, Susceptibility Type, 2 phenotype (8.3e-07), strongly suggesting that the variant is benign. The variant, c.741_755del15 or equivalent protein level changes, have been reported in the literature in individuals affected with Neuroblastoma (e.g. Raabe_2008), however without providing evidence for causality. Similar 5 alanine deletion variants have also been reported in patients affected with Hirschsprung disease, with some of them noting mild neonatal respiratory disorders (Di Zanni_2017). Authors of this study also reported experimental evidence evaluating the impact of contractions of the polyalanine tract, and demonstrated that the -5Ala variant resulted in ~95% transactivation response compared to the WT on RET promoter, while greater contractions (-7Ala and -13Ala) resulted in significantly lower transactivation values (Di Zanni_2017), therefore authors of this study proposed that contractions of the 20 alanine stretch of the PHOX2B gene could increase the susceptibility to Hirschsprung disease (with mild neonatal respiratory disorders). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Dec 14, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala256_Ala260del (also known as p.Ala241[15]) in exon 3 of PHOX2B: This varian t is common in the general population and therefore believed to be benign (Gener eviews: www.ncbi.nlm.nih.gov/books/NBK1427/#ondine.Molecular_Genetics). It was d etected in 2% (63/3266) of East Asian chromosomes, including 2 homozygotes, by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 75006915). This variant represents a deletion of 5 alanine amino acids within a repeat sequence in this gene, for a total of 15 total repeats (The predominant n ormal allele contains 20 repeats). -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PHOX2B: BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17637745, 14566559) -

Hereditary cancer-predisposing syndrome

Benign:2

Oct 26, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 31, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Haddad syndrome

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.96

Mutation Taster

=193/7

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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