rs757020181

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.738_776delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC(p.Ala247_Ala259del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,288,314 control chromosomes in the GnomAD database, including 58 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. A246A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 58 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.23

Publications

1 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 4-41745975-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC-T is Benign according to our data. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000845 (125/147848) while in subpopulation AMR AF = 0.00328 (49/14952). AF 95% confidence interval is 0.00255. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.738_776delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC	p.Ala247_Ala259del	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.738_776delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC	p.Ala247_Ala259del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.19_57delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000839

AC:

124

AN:

147736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000832

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000425

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.000214

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.000467

Gnomad OTH

AF:

0.000980

GnomAD2 exomes

AF:

0.00280

AC:

143

AN:

51026

AF XY:

0.00228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000867

Gnomad OTH exome

AF:

0.000924

GnomAD4 exome

AF:

0.000609

AC:

694

AN:

1140466

Hom.:

AF XY:

0.000620

AC XY:

342

AN XY:

551168

show subpopulations

African (AFR)

AF:

0.000552

AC:

AN:

23570

American (AMR)

AF:

0.0165

AC:

178

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16722

East Asian (EAS)

AF:

0.000558

AC:

AN:

25104

South Asian (SAS)

AF:

0.00273

AC:

AN:

30012

European-Finnish (FIN)

AF:

0.000254

AC:

AN:

31492

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

3286

European-Non Finnish (NFE)

AF:

0.000373

AC:

356

AN:

954332

Other (OTH)

AF:

0.000842

AC:

AN:

45146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.589

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000845

AC:

125

AN:

147848

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

AN XY:

72020

show subpopulations

African (AFR)

AF:

0.000854

AC:

AN:

40988

American (AMR)

AF:

0.00328

AC:

AN:

14952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.000426

AC:

AN:

4692

South Asian (SAS)

AF:

0.000420

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.000214

AC:

AN:

9362

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000467

AC:

AN:

66430

Other (OTH)

AF:

0.000970

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000367

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PHOX2B: BS2 -

Feb 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26375764) -

Hereditary cancer-predisposing syndrome

Benign:2

Oct 26, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 08, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Other strong data supporting benign classification -

Haddad syndrome

Benign:1

Dec 02, 2024

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

3.2

Mutation Taster

=198/2

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