rs771383153

Variant names:

• chr4-41745993-CGCCGCCGCCGCTGCCGCG-C
• rs771383153
• NM_003924.4:c.741_758delCGCGGCAGCGGCGGCGGC

Your query was ambiguous. Multiple possible variants found:

• chr4-41745993-CGCCGCCGCCGCTGCCGCG-C
• chr4-41745993-CGCCGCCGCCGCTGCCGCG-CGCCGCCGCCGCTGCCGCGGCCGCCGCCGCTGCCGCG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.14
• Publications: 2 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, 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 227016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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	c.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*22_*39delCGCGGCAGCGGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000763 AC: 112 AN: 146712 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00179 AC: 24 AN: 13430 AF XY: 0.00110

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 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.: 15 AF XY: 0.000514 AC XY: 261 AN XY: 507794

African (AFR) AF: 0.00157 AC: 33 AN: 21018

American (AMR) AF: 0.00458 AC: 34 AN: 7422

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 80 AN: 12740

East Asian (EAS) AF: 0.000405 AC: 9 AN: 22220

South Asian (SAS) AF: 0.00216 AC: 46 AN: 21258

European-Finnish (FIN) AF: 0.000713 AC: 18 AN: 25228

Middle Eastern (MID) AF: 0.000708 AC: 2 AN: 2824

European-Non Finnish (NFE) AF: 0.000331 AC: 301 AN: 908124

Other (OTH) AF: 0.00107 AC: 44 AN: 41096

GnomAD4 genome AF: 0.000783 AC: 115 AN: 146816 Hom.: 0 Cov.: 32 AF XY: 0.000937 AC XY: 67 AN XY: 71486

African (AFR) AF: 0.00127 AC: 52 AN: 40846

American (AMR) AF: 0.00172 AC: 25 AN: 14494

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 14 AN: 3412

East Asian (EAS) AF: 0.000798 AC: 4 AN: 5014

South Asian (SAS) AF: 0.000421 AC: 2 AN: 4750

European-Finnish (FIN) AF: 0.000221 AC: 2 AN: 9046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000227 AC: 15 AN: 66046

Other (OTH) AF: 0.000492 AC: 1 AN: 2032

Alfa AF: 0.000674 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

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

-

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. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHOX2B: BS1, BS2 -

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
PhyloP100		2.1
Mutation Taster		=191/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs771383153; hg19: chr4-41748010; COSMIC: COSV108088129;