4-41745975-T-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_003924.4(PHOX2B):c.776_777insGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC(p.Ala248_Ala260dup) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
PHOX2B
NM_003924.4 inframe_insertion
NM_003924.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.60
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a region_of_interest Disordered (size 30) in uniprot entity PHX2B_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_003924.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-41745975-T-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC is Pathogenic according to our data. Variant chr4-41745975-T-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 984923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.776_777insGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC | p.Ala248_Ala260dup | inframe_insertion | 3/3 | ENST00000226382.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.776_777insGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC | p.Ala248_Ala260dup | inframe_insertion | 3/3 | 1 | NM_003924.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2018 | The p.Ala241[33] pathogenic mutation, located in coding exon 3 of the PHOX2B gene, results from an expansion of the polyalanine repeat region from 20 to 33 repeats. This expansion mutation is associated with congenital central hypoventilation syndrome (Matera I et al. J. Med. Genet., 2004 May;41:373-80). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Congenital central hypoventilation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jan 16, 2020 | This variant is located within the polyalanine tract in exon 3 of the PHOX2B gene and is expected to result in an expansion event. Repeat expansions within the polyalanine tract in the PHOX2B gene are an established mechanism of disease and have been previously reported in patients with Congenital Central Hypoventilation Syndrome (PMID: 12640453, 14566559, 14608649, 15121777). Analysis of the parental samples showed the mother is negative and the father is negative for this variant. Orthogonal confirmation is pending. Based on the available evidence, the c.738_776dup (p.Ala248_Ala260dup) variant is classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at