Variant 4-41745967-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003924.4(PHOX2B):c.785G>T(p.Gly262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,342,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 1.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20323712).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.785G>T	p.Gly262Val	missense_variant	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.785G>T	p.Gly262Val	missense_variant	3/3	1	NM_003924.4	ENSP00000226382	P1

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149510

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1193402

Hom.:

Cov.:

AF XY:

0.00000862

AC XY:

AN XY:

580288

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000643

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000102

Gnomad4 OTH exome

AF:

0.0000210

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149510

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72864

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000195

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital central hypoventilation

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 25, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2024	The p.G262V variant (also known as c.785G>T), located in coding exon 3 of the PHOX2B gene, results from a G to T substitution at nucleotide position 785. The glycine at codon 262 is replaced by valine, an amino acid with dissimilar properties. This alteration has been identified in trans with a polyalanine repeat expansion mutation (PARM) with 24 alanines in a 3 year old diagnosed with congenital central hypoventilation syndrome (Sivan Y et al. Am J Med Genet A, 2019 03;179:503-506). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 14, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous or homozygous state in individuals with CCHS, both of whom had multiple unaffected relatives also heterozygous for the variant (Sivan et al., 2023); This variant is associated with the following publications: (PMID: 30672101, 37373665, 33958749) -

Haddad syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 262 of the PHOX2B protein (p.Gly262Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital central hypoventilation syndrome (PMID: 30672101). ClinVar contains an entry for this variant (Variation ID: 467746). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.22

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.040

REVEL

Benign

0.27

Sift

Benign

0.047

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.36

MutPred

0.41

Gain of helix (P = 0.0082);

MVP

0.67

MPC

1.4

ClinPred

0.032

GERP RS

2.1

Varity_R

0.10

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

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