dbSNP rs752879767: PHOX2B:p.Gly278_Pro279del (chr4-41745914-TGGGGCC-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The ENST00000226382.4(PHOX2B):c.832_837delGGCCCC(p.Gly278_Pro279del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000688 in 1,453,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G278G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PHOX2B
ENST00000226382.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.14

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Haddad syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
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

PHOX2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000226382.4.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000226382.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	NM_003924.4	MANE Select	c.832_837delGGCCCC	p.Gly278_Pro279del	conservative_inframe_deletion	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.832_837delGGCCCC	p.Gly278_Pro279del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000226382.2
	PHOX2B	ENST00000510424.2	TSL:3	n.113_118delGGCCCC		downstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453026

Hom.:

AF XY:

0.00

AC XY:

AN XY:

722896

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32596

American (AMR)

AF:

0.00

AC:

AN:

44150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

38946

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108262

Other (OTH)

AF:

0.00

AC:

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over