4-41745972-AGCTGCCGCCGCTGCC-AGCTGCCGCCGCTGCCGCTGCCGCCGCTGCC

Variant names:

• chr4-41745972-A-AGCTGCCGCCGCTGCC
• rs761018157
• NM_003924.4:c.765_779dupGGCAGCGGCGGCAGC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM4 PP5_Very_Strong

The NM_003924.4(PHOX2B):​c.765_779dupGGCAGCGGCGGCAGC​(p.Ala256_Ala260dup) 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000581758: 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" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHOX2B NM_003924.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.633
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000581758: 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)
• PM4: Nonframeshift variant in NON repetitive region in NM_003924.4.
• PP5: Variant 4-41745972-A-AGCTGCCGCCGCTGCC is Pathogenic according to our data. Variant chr4-41745972-A-AGCTGCCGCCGCTGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 429242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	NM_003924.4	MANE Select	c.765_779dupGGCAGCGGCGGCAGC	p.Ala256_Ala260dup	disruptive_inframe_insertion	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.765_779dupGGCAGCGGCGGCAGC	p.Ala256_Ala260dup	disruptive_inframe_insertion	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.*46_*60dupGGCAGCGGCGGCAGC		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1179708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 572888

African (AFR) AF: 0.00 AC: 0 AN: 25086

American (AMR) AF: 0.00 AC: 0 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18228

East Asian (EAS) AF: 0.00 AC: 0 AN: 29218

South Asian (SAS) AF: 0.00 AC: 0 AN: 34654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 972502

Other (OTH) AF: 0.00 AC: 0 AN: 47044

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital central hypoventilation (2)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	PHOX2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=74/26	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs761018157; hg19: chr4-41747989;