NM_003924.4:c.756_776delGGCGGCAGCGGCAGCGGCGGC

Variant names:

Variant summary

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

The NM_003924.4(PHOX2B):c.756_776delGGCGGCAGCGGCAGCGGCGGC(p.Ala253_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 0.00147 in 1,288,110 control chromosomes in the GnomAD database, including 37 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. A252A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 34 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

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, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Haddad syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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-TGCCGCCGCTGCCGCTGCCGCC-T is Benign according to our data. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239593.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 = 0.00189 (279/147844) while in subpopulation AMR AF = 0.00869 (130/14952). AF 95% confidence interval is 0.00748. There are 3 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 279 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	NM_003924.4	MANE Select	c.756_776delGGCGGCAGCGGCAGCGGCGGC	p.Ala253_Ala259del	disruptive_inframe_deletion	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.756_776delGGCGGCAGCGGCAGCGGCGGC	p.Ala253_Ala259del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.37_57delGGCGGCAGCGGCAGCGGCGGC		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

279

AN:

147732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00574

Gnomad SAS

AF:

0.00336

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0162

Gnomad NFE

AF:

0.000873

Gnomad OTH

AF:

0.00294

GnomAD2 exomes

AF:

0.00825

AC:

421

AN:

51026

AF XY:

0.00846

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0280

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.0436

Gnomad FIN exome

AF:

0.000274

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00739

GnomAD4 exome

AF:

0.00141

AC:

1612

AN:

1140266

Hom.:

AF XY:

0.00157

AC XY:

867

AN XY:

551056

show subpopulations

African (AFR)

AF:

0.00306

AC:

AN:

23556

American (AMR)

AF:

0.0144

AC:

155

AN:

10796

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

16718

East Asian (EAS)

AF:

0.0125

AC:

312

AN:

25030

South Asian (SAS)

AF:

0.00800

AC:

240

AN:

29994

European-Finnish (FIN)

AF:

0.000349

AC:

AN:

31488

Middle Eastern (MID)

AF:

0.00517

AC:

AN:

3286

European-Non Finnish (NFE)

AF:

0.000724

AC:

691

AN:

954272

Other (OTH)

AF:

0.00199

AC:

AN:

45126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00189

AC:

279

AN:

147844

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

152

AN XY:

72018

show subpopulations

African (AFR)

AF:

0.000903

AC:

AN:

40986

American (AMR)

AF:

0.00869

AC:

130

AN:

14952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00575

AC:

AN:

4694

South Asian (SAS)

AF:

0.00336

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9362

Middle Eastern (MID)

AF:

0.0174

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000873

AC:

AN:

66428

Other (OTH)

AF:

0.00291

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

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:

0.00141

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

not specified (2)

Haddad syndrome (1)

PHOX2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=195/5

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over