4-41745993-CGCCGCCGCCGCTGCCGCG-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003924.4(PHOX2B):c.741_758delCGCGGCAGCGGCGGCGGC(p.Ala248_Ala253del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,208,746 control chromosomes in the GnomAD database, including 15 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 15 hom. )

Consequence

PHOX2B
NM_003924.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.14

Publications

2 publications found

Variant links:

COSMIC-nc: COSV108088129

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

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

BP6

Variant 4-41745993-CGCCGCCGCCGCTGCCGCG-C is Benign according to our data. Variant chr4-41745993-CGCCGCCGCCGCTGCCGCG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000783 (115/146816) while in subpopulation AMR AF = 0.00172 (25/14494). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 115 AD gene.

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.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	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.741_758delCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.22_39delCGCGGCAGCGGCGGCGGC		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

112

AN:

146712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00173

Gnomad ASJ

AF:

0.00410

Gnomad EAS

AF:

0.000795

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.000221

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000227

Gnomad OTH

AF:

0.000498

GnomAD2 exomes

AF:

0.00179

AC:

AN:

13430

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.00633

Gnomad AMR exome

AF:

0.00709

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.000761

Gnomad OTH exome

AF:

0.00318

GnomAD4 exome

AF:

0.000534

AC:

567

AN:

1061930

Hom.:

AF XY:

0.000514

AC XY:

261

AN XY:

507794

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

21018

American (AMR)

AF:

0.00458

AC:

AN:

7422

Ashkenazi Jewish (ASJ)

AF:

0.00628

AC:

AN:

12740

East Asian (EAS)

AF:

0.000405

AC:

AN:

22220

South Asian (SAS)

AF:

0.00216

AC:

AN:

21258

European-Finnish (FIN)

AF:

0.000713

AC:

AN:

25228

Middle Eastern (MID)

AF:

0.000708

AC:

AN:

2824

European-Non Finnish (NFE)

AF:

0.000331

AC:

301

AN:

908124

Other (OTH)

AF:

0.00107

AC:

AN:

41096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000783

AC:

115

AN:

146816

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

AN XY:

71486

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

40846

American (AMR)

AF:

0.00172

AC:

AN:

14494

Ashkenazi Jewish (ASJ)

AF:

0.00410

AC:

AN:

3412

East Asian (EAS)

AF:

0.000798

AC:

AN:

5014

South Asian (SAS)

AF:

0.000421

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.000221

AC:

AN:

9046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.000227

AC:

AN:

66046

Other (OTH)

AF:

0.000492

AC:

AN:

2032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000674

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Haddad syndrome (1)

Neuroblastoma, susceptibility to, 2;C5562075:Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=191/9

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over