Variant 4-41748391-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_003924.4(PHOX2B):c.220C>A(p.Gln74Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.76

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:

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

PHOX2B-AS1 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.220C>A	p.Gln74Lys	missense_variant	1/3	ENST00000226382.4	NP_003915.2
PHOX2B-AS1	XR_001741671.2 linkuse as main transcript	n.43G>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.220C>A	p.Gln74Lys	missense_variant	1/3	1	NM_003924.4	ENSP00000226382	P1
PHOX2B-AS1	ENST00000508038.1 linkuse as main transcript	n.99G>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250194

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.60

Sift

Uncertain

0.0070

Sift4G

Benign

0.19

Polyphen

0.90

Vest4

0.53

MutPred

0.30

Gain of ubiquitination at Q74 (P = 0.009);

MVP

0.94

MPC

2.2

ClinPred

0.79

GERP RS

5.6

Varity_R

0.57

gMVP

0.93

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over