rs17885216

Variant names:

• chr4-41746200-G-A
• rs17885216
• NM_003924.4:c.552C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003924.4(PHOX2B):​c.552C>T​(p.Ser184Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.0112 in 1,613,744 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (111 hom.)
• Consequence: PHOX2B NM_003924.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 6.43

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-41746200-G-A is Benign according to our data. Variant chr4-41746200-G-A is described in ClinVar as [Benign]. Clinvar id is 227015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41746200-G-A is described in Lovd as [Benign]. Variant chr4-41746200-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00999 (1520/152178) while in subpopulation NFE AF= 0.0118 (800/67990). AF 95% confidence interval is 0.0111. There are 14 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1520 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.552C>T	p.Ser184Ser	synonymous_variant	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.552C>T	p.Ser184Ser	synonymous_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.373C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1520 AN: 152060 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00848 AC: 2129 AN: 250962 Hom.: 11 AF XY: 0.00821 AC XY: 1114 AN XY: 135712

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.00680

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0113 AC: 16528 AN: 1461566 Hom.: 111 Cov.: 32 AF XY: 0.0109 AC XY: 7927 AN XY: 727128

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.00733

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00999 AC: 1520 AN: 152178 Hom.: 14 Cov.: 32 AF XY: 0.00894 AC XY: 665 AN XY: 74416

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0118 Hom.: 7

Bravo AF: 0.0112

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PHOX2B c.552C>T (p.Ser184Ser) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create a novel ESE site of SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1028/120536 control chromosomes (4 homozygotes) at a frequency of 0.0085286, which is approximately 10234 times the estimated maximal expected allele frequency of a pathogenic PHOX2B variant (0.0000008), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHOX2B: BP4, BP7, BS1, BS2 -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser184Ser in exon 3 of PHOX2B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1.2% (765/66160) of European chromosomes, including 1 homozygote by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs17885216). -

Nov 30, 2017

GeneDx

Significance: 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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuroblastoma, susceptibility to, 2 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Haddad syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 20, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Congenital central hypoventilation Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.8
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17885216; hg19: chr4-41748217;