chr4-41745975-T-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC

Position:

• chr4-41745975-T-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs757020181; hg19: chr4-41747992;