rs745709595

Variant names:

• chr4-41745955-G-A
• rs745709595
• NM_003924.4:c.797C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-41745955-G-A
• chr4-41745955-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003924.4(PHOX2B):​c.797C>T​(p.Ala266Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A266S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: PHOX2B NM_003924.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.45
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23991314).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. 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.797C>T	p.Ala266Val	missense	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.797C>T	p.Ala266Val	missense	Exon 3 of 3	ENSP00000226382.2
	PHOX2B	ENST00000510424.2	TSL:3	n.*78C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000678 AC: 1 AN: 147436 AF XY: 0.00

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303484 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 643464

African (AFR) AF: 0.0000356 AC: 1 AN: 28102

American (AMR) AF: 0.00 AC: 0 AN: 31144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22046

East Asian (EAS) AF: 0.00 AC: 0 AN: 31076

South Asian (SAS) AF: 0.00 AC: 0 AN: 60966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1030324

Other (OTH) AF: 0.00 AC: 0 AN: 52216

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000868 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Haddad syndrome Uncertain:1

Jan 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with valine at codon 266 of the PHOX2B protein (p.Ala266Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs745709595, ExAC 0.02%). This variant has not been reported in the literature in individuals with PHOX2B-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A266V variant (also known as c.797C>T), located in coding exon 3 of the PHOX2B gene, results from a C to T substitution at nucleotide position 797. The alanine at codon 266 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.020	D
Sift4G	Benign	0.18	T
Polyphen		0.84	P
Vest4		0.29
MutPred		0.35		Gain of sheet (P = 0.0043)
MVP		0.81
MPC		1.1
ClinPred		0.19	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.58
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs745709595; hg19: chr4-41747972;