rs757850760

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.735_767delGGCGGCCGCGGCAGCGGCGGCGGCGGCAGCGGC(p.Ala246_Ala256del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,255,482 control chromosomes in the GnomAD database, including 26 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. A245A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 26 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.23

Publications

0 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 4-41745984-TGCCGCTGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is Benign according to our data. Variant chr4-41745984-TGCCGCTGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 467741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000819 (12/146574) while in subpopulation SAS AF = 0.00191 (9/4700). AF 95% confidence interval is 0.000999. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 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.735_767delGGCGGCCGCGGCAGCGGCGGCGGCGGCAGCGGC	p.Ala246_Ala256del	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.735_767delGGCGGCCGCGGCAGCGGCGGCGGCGGCAGCGGC	p.Ala246_Ala256del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.16_48delGGCGGCCGCGGCAGCGGCGGCGGCGGCAGCGGC		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000819

AC:

AN:

146472

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00191

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000788

AC:

AN:

35526

AF XY:

0.00116

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:

0.00

Gnomad NFE exome

AF:

0.0000606

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

164

AN:

1108908

Hom.:

AF XY:

0.000236

AC XY:

126

AN XY:

533988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22458

American (AMR)

AF:

0.00

AC:

AN:

9086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15324

East Asian (EAS)

AF:

0.0000432

AC:

AN:

23154

South Asian (SAS)

AF:

0.00511

AC:

134

AN:

26230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3120

European-Non Finnish (NFE)

AF:

0.0000214

AC:

AN:

936702

Other (OTH)

AF:

0.000207

AC:

AN:

43554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.671

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000819

AC:

AN:

146574

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

71328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40776

American (AMR)

AF:

0.00

AC:

AN:

14570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

4628

South Asian (SAS)

AF:

0.00191

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000303

AC:

AN:

66108

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Haddad syndrome (1)

not provided (1)

PHOX2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

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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