rs1433654836

chr4-41746058-G-Cchr4-41746058-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003924.4(PHOX2B):c.694C>G(p.Pro232Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000677 in 147,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P232R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
• Consequence: PHOX2B NM_003924.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.72

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13103938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.694C>G	p.Pro232Ala	missense_variant	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.694C>G	p.Pro232Ala	missense_variant	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2	n.515C>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00000677 AC: 1 AN: 147766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000677 AC: 1 AN: 147766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72028

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Haddad syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2023

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 232 of the PHOX2B protein (p.Pro232Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 970177). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The p.P232A variant (also known as c.694C>G), located in coding exon 3 of the PHOX2B gene, results from a C to G substitution at nucleotide position 694. The proline at codon 232 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.84
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.25		Loss of glycosylation at P232 (P = 0.0538);
MVP		0.70
MPC		1.1
ClinPred		0.093	T
GERP RS		2.1
Varity_R		0.072
gMVP		0.63

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: rs1433654836; hg19: chr4-41748075; COSMIC: COSV56928894; COSMIC: COSV56928894;