NM_003924.4:c.694C>G

Variant names:

• chr4-41746058-G-C
• rs1433654836
• NM_003924.4:c.694C>G

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.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. 15/22 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:3
• Conservation: PhyloP100: 2.72
• 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=0.13103938).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	NM_003924.4	MANE Select	c.694C>G	p.Pro232Ala	missense	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.694C>G	p.Pro232Ala	missense	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.515C>G		non_coding_transcript_exon	Exon 3 of 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

African (AFR) AF: 0.00 AC: 0 AN: 40542

American (AMR) AF: 0.00 AC: 0 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4948

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66758

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Haddad syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Neuroblastoma, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.7
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
Mutation Taster		=91/9	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: rs1433654836; hg19: chr4-41748075; COSMIC: COSV56928894; COSMIC: COSV56928894;