Genetic Variant PHOX2B:p.Ala244_Ala250dup (chr4-41746002-C-CGCTGCCGCGGCCGCCGCCGCT) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP3

The NM_003924.4(PHOX2B):c.729_749dupAGCGGCGGCGGCCGCGGCAGC(p.Ala244_Ala250dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.308

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-41746002-C-CGCTGCCGCGGCCGCCGCCGCT is Pathogenic according to our data. Variant chr4-41746002-C-CGCTGCCGCGGCCGCCGCCGCT is described in ClinVar as [Pathogenic]. Clinvar id is 506167.Status of the report is criteria_provided_single_submitter, 1 stars.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.729_749dupAGCGGCGGCGGCCGCGGCAGC	p.Ala244_Ala250dup	disruptive_inframe_insertion	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.729_749dupAGCGGCGGCGGCCGCGGCAGC	p.Ala244_Ala250dup	disruptive_inframe_insertion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.10_30dupAGCGGCGGCGGCCGCGGCAGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1015758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

484012

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital central hypoventilation

Pathogenic:1

Oct 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala241[27] variant in PHOX2B is a well-established pathogenic variant for CCHS, which has been reported in >200 affected individuals across multiple studi es (Weese-Mayer 2010). This variant is a 21bp duplication within a polyalanine t ract in exon 3 of the PHOX2B gene, resulting in an expansion to a total of 27 al anine residues. It frequently occurs de novo, though autosomal dominant inherita nce and somatic mosaicism have also been reported. In summary, this variant meet s our criteria to be classified as pathogenic for CCHS in an autosomal dominant manner. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

4-41746002-CGCTGCCGCGGCCGCCGCCGCT-CGCTGCCGCGGCCGCCGCCGCTGCTGCCGCGGCCGCCGCCGCT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over