rs749694204

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_003924.4(PHOX2B):c.735_761delGGCGGCCGCGGCAGCGGCGGCGGCGGC(p.Ala246_Ala254del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,235,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.12

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, 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is Benign according to our data. Variant chr4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 467740.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.735_761delGGCGGCCGCGGCAGCGGCGGCGGCGGC	p.Ala246_Ala254del	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.735_761delGGCGGCCGCGGCAGCGGCGGCGGCGGC	p.Ala246_Ala254del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.16_42delGGCGGCCGCGGCAGCGGCGGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000477

AC:

AN:

146666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000689

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000422

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00149

GnomAD2 exomes

AF:

0.0000465

AC:

AN:

21500

AF XY:

0.0000757

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:

0.000108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000257

AC:

AN:

1089222

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

522656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22026

American (AMR)

AF:

0.000478

AC:

AN:

8376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14028

East Asian (EAS)

AF:

0.00

AC:

AN:

24026

South Asian (SAS)

AF:

0.0000428

AC:

AN:

23382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27446

Middle Eastern (MID)

AF:

0.000672

AC:

AN:

2978

European-Non Finnish (NFE)

AF:

0.0000195

AC:

AN:

924342

Other (OTH)

AF:

0.0000704

AC:

AN:

42618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000477

AC:

AN:

146666

Hom.:

Cov.:

AF XY:

0.0000841

AC XY:

AN XY:

71376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40666

American (AMR)

AF:

0.0000689

AC:

AN:

14524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.000422

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66044

Other (OTH)

AF:

0.00149

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Haddad syndrome

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=194/6

polymorphism

(source)

Splicing

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

Publications

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rs749694204

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