rs757020181
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_003924.4(PHOX2B):c.738_776delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC(p.Ala247_Ala259del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,288,314 control chromosomes in the GnomAD database, including 58 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 58 hom. )
Consequence
PHOX2B
NM_003924.4 disruptive_inframe_deletion
NM_003924.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.23
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
Variant 4-41745975-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC-T is Benign according to our data. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 239590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCCGCCGCCGCTGCCGCGGCC-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000845 (125/147848) while in subpopulation AMR AF= 0.00328 (49/14952). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 125 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PHOX2B | ENST00000226382.4 | c.738_776delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC | p.Ala247_Ala259del | disruptive_inframe_deletion | Exon 3 of 3 | 1 | NM_003924.4 | ENSP00000226382.2 | ||
| PHOX2B | ENST00000510424.2 | n.*19_*57delGGCCGCGGCAGCGGCGGCGGCGGCAGCGGCAGCGGCGGC | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes 0.000839 AC: 124AN: 147736Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00280 AC: 143AN: 51026Hom.: 26 AF XY: 0.00228 AC XY: 70AN XY: 30750
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GnomAD4 exome AF: 0.000609 AC: 694AN: 1140466Hom.: 58 AF XY: 0.000620 AC XY: 342AN XY: 551168
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GnomAD4 genome 0.000845 AC: 125AN: 147848Hom.: 0 Cov.: 32 AF XY: 0.000903 AC XY: 65AN XY: 72020
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Feb 14, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is associated with the following publications: (PMID: 26375764) -
Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PHOX2B: BS2 -
Hereditary cancer-predisposing syndrome Benign:2
Oct 26, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation
- -
Sep 08, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Other strong data supporting benign classification -
Haddad syndrome Benign:1
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at