rs771383153

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003924.4(PHOX2B):c.741_758delCGCGGCAGCGGCGGCGGC(p.Ala248_Ala253del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,208,746 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 15 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.14

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 Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

BP6

Variant 4-41745993-CGCCGCCGCCGCTGCCGCG-C is Benign according to our data. Variant chr4-41745993-CGCCGCCGCCGCTGCCGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 227016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745993-CGCCGCCGCCGCTGCCGCG-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000783 (115/146816) while in subpopulation AMR AF= 0.00172 (25/14494). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000226382.4	NP_003915.2	Q99453

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 link	c.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.22_39delCGCGGCAGCGGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

112

AN:

146712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00173

Gnomad ASJ

AF:

0.00410

Gnomad EAS

AF:

0.000795

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.000221

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000227

Gnomad OTH

AF:

0.000498

GnomAD3 exomes

AF:

0.00179

AC:

AN:

13430

Hom.:

AF XY:

0.00110

AC XY:

AN XY:

8164

show subpopulations

Gnomad AFR exome

AF:

0.00633

Gnomad AMR exome

AF:

0.00709

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00277

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.000761

Gnomad OTH exome

AF:

0.00318

GnomAD4 exome

AF:

0.000534

AC:

567

AN:

1061930

Hom.:

AF XY:

0.000514

AC XY:

261

AN XY:

507794

show subpopulations

Gnomad4 AFR exome

AF:

0.00157

Gnomad4 AMR exome

AF:

0.00458

Gnomad4 ASJ exome

AF:

0.00628

Gnomad4 EAS exome

AF:

0.000405

Gnomad4 SAS exome

AF:

0.00216

Gnomad4 FIN exome

AF:

0.000713

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.000783

AC:

115

AN:

146816

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

AN XY:

71486

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00172

Gnomad4 ASJ

AF:

0.00410

Gnomad4 EAS

AF:

0.000798

Gnomad4 SAS

AF:

0.000421

Gnomad4 FIN

AF:

0.000221

Gnomad4 NFE

AF:

0.000227

Gnomad4 OTH

AF:

0.000492

Alfa

AF:

0.000674

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant represents a benign variant of the poly-alanine repeat in PHOX2 (14 of 20 repeat units). It is benign per Development and Validation Report for PH OX2B "PHOX2b contains 2 polyalanine repeats of 9 alanines and 20 alanines within exon 3. Expansions within the 20 alanine stretch are pathogenic and cause Centr al Hyopventilation Syndrome but cannot be accurately detected via NGS". Variant s of 9, 13,14 and 15 repeat units have been observed but are benign (genereviews ) -

Oct 27, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PHOX2B c.741_758del18 (p.Ala255_Ala260del) results in an in-frame deletion that is predicted to remove 6 Alanines in a Alanine repeat region from the encoded protein. The variant allele was found at a frequency of 0.0018 in 13430 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2144 fold of the estimated maximal expected allele frequency for a pathogenic variant in PHOX2B causing Neuroblastoma, Susceptibility Type, 2 phenotype (8.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.741_758del18 in individuals affected with Neuroblastoma, Susceptibility Type, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 14, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHOX2B: BS1, BS2 -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PHOX2B p.Ala248_Ala253del variant was not identified in the literature but was identified in dbSNP (ID: rs771383153) and ClinVar (classified as likely benign by Prevention Genetics, GeneDx, Ambry Genetics, and Invitae; and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 40 of 39290 chromosomes (2 homozygous) at a frequency of 0.001018 (Genome Aggregation Database March 6, 2019, v2.1.1). This variant is an in-frame deletion resulting in the removal of alanine residues from codons 248 to 253; this deletion occurs within an alanine repeat region. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Apr 16, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 22, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

Benign:1

Feb 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Haddad syndrome

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over