Variant 4-41745975-T-TGCCGCCGCTGCCGCTGCCGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_003924.4(PHOX2B):c.776_777insGGCGGCAGCGGCAGCGGCGGC(p.Ala254_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOX2B
NM_003924.4 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.60

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-41745975-T-TGCCGCCGCTGCCGCTGCCGCC is Pathogenic according to our data. Variant chr4-41745975-T-TGCCGCCGCTGCCGCTGCCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 452239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.776_777insGGCGGCAGCGGCAGCGGCGGC	p.Ala254_Ala260dup	inframe_insertion	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.776_777insGGCGGCAGCGGCAGCGGCGGC	p.Ala254_Ala260dup	inframe_insertion	3/3	1	NM_003924.4	ENSP00000226382	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

8.77e-7

AC:

AN:

1140480

Hom.:

Cov.:

AF XY:

0.00000181

AC XY:

AN XY:

551176

show subpopulations

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:

0.00000105

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2;C5562075:Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2023

Duplication of 7 alanine residues in the second polyalanine tract, resulting in a total of 27 alanine residues.; Polyalanine repeat expansion of 26 or more repeats have been reported in association with congenital central hypoventilation syndrome (PMID: 20301600; 20208042); Published functional evidence indicate that expanded PHOX2B protein forms ubiquitin positive inclusions, which sequester wild-type PHOX2B, resulting in reduced transcriptional and binding activity of wild-type protein and possibly supporting a dominant-negative effect (PMID 22307522; 23103552); De novo variant with confirmed parentage in a patient with Congenital Central Hypoventilation Syndrome (CCHS) and Hirschsprung disease previously tested at GeneDx and as an apparently de novo variant in multiple patients in the published literature with CCHS (PMID: 12640453; 15121777); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23231723, 22437207, 18079495, 30850150, 12640453, 15121777, 20456320, 15860752, 22307522, 20301600, 20208042) -

PHOX2B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

The PHOX2B c.756_776dup21 variant is predicted to result in an in-frame duplication (p.Ala254_Ala260dup). This variant has previously been reported in multiple individuals with congenital central hypoventilation syndrome (CCHS) (Serra et al. 2010. PubMed ID: 20456320). This duplication causes an expansion of the polyalanine repeat region from 20 repeats (normal) to 27 repeats; repeat expansions of similar size have been documented to be causative for CCHS (Lai and Schroer. 2008. PubMed ID: 18230845; Trivedi et al. 2011. PubMed ID: 21076974). This variant is not present in a large population database and has been interpreted as Pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/452239/). Taken together, we interpret this variant as pathogenic. -

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

This variant is located within the polyalanine tract in exon 3 of the PHOX2B gene and causes an in-frame duplication resulting in an expansion event. An alternative nomenclature for this variant is p.Ala241[27], which corresponds to a 27 polyalanine repeat expansion (PMID: 20301600). 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). This variant has been previously reported as a heterozygous change in multiple individuals with Congenital Central Hypoventilation Syndrome (PMID: 20456320). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating that this variant likely occurred as a de novo event. Based on the available evidence, the c.756_776dup (p.Ala254_Ala260dup) variant is classified as Pathogenic. -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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