4-41745996-CGCCGCCGCTGCCGCG-CGCCGCCGCTGCCGCGGCCGCCGCTGCCGCG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP3

The NM_003924.4(PHOX2B):​c.741_755dupCGCGGCAGCGGCGGC​(p.Ala248_Ala252dup) 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)

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.963
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-41745996-C-CGCCGCCGCTGCCGCG is Pathogenic according to our data. Variant chr4-41745996-C-CGCCGCCGCTGCCGCG is described in ClinVar as [Pathogenic]. Clinvar id is 802070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP3
Nonframeshift variant in repetitive region in NM_003924.4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PHOX2BNM_003924.4 linkc.741_755dupCGCGGCAGCGGCGGC p.Ala248_Ala252dup 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
PHOX2BENST00000226382.4 linkc.741_755dupCGCGGCAGCGGCGGC p.Ala248_Ala252dup disruptive_inframe_insertion Exon 3 of 3 1 NM_003924.4 ENSP00000226382.2 Q99453
PHOX2BENST00000510424.2 linkn.*22_*36dupCGCGGCAGCGGCGGC downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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
Nov 16, 2020
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Ala241[25] pathogenic mutation, located in coding exon 3 of the PHOX2B gene, results from an expansion of the polyalanine repeat region from 20 to 25 repeats. This expansion mutation is associated with congenital central hypoventilation syndrome (Amiel J et al. Nat. Genet., 2003 Apr;33:459-61; 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
May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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.

Other links and lift over

dbSNP: rs775006915; hg19: chr4-41748013; API