rs1553898212

Positions:

• chr4-41748441-C-T

Variant summary

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

The ENST00000226382.4(PHOX2B):​c.170G>A​(p.Cys57Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C57C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B ENST00000226382.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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-AS1 (HGNC:40457): (PHOX2B antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.170G>A	p.Cys57Tyr	missense_variant	1/3	ENST00000226382.4	NP_003915.2
PHOX2B-AS1	XR_001741671.2	n.93C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.170G>A	p.Cys57Tyr	missense_variant	1/3	1	NM_003924.4	ENSP00000226382	P1
PHOX2B-AS1	ENST00000508038.1	n.149C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Haddad syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PHOX2B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 57 of the PHOX2B protein (p.Cys57Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.64
Sift	Benign	0.052	T
Sift4G	Benign	0.52	T
Polyphen		0.98	D
Vest4		0.71
MutPred		0.22		Gain of glycosylation at S59 (P = 0.0639);
MVP		0.59
MPC		2.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.58
gMVP		0.94

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: rs1553898212; hg19: chr4-41750458;