19-41357947-GC-TT
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_030578.4(B9D2):c.163_164delinsAA(p.Ala55Asn) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A55D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Consequence
B9D2
NM_030578.4 missense
NM_030578.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.88
Genes affected
B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]
TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a chain B9 domain-containing protein 2 (size 174) in uniprot entity B9D2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_030578.4
PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
B9D2 | NM_030578.4 | c.163_164delinsAA | p.Ala55Asn | missense_variant | 3/4 | ENST00000243578.8 | |
B9D2 | XM_011527349.3 | c.163_164delinsAA | p.Ala55Asn | missense_variant | 3/4 | ||
B9D2 | XM_011527350.3 | c.4_5delinsAA | p.Ala2Asn | missense_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
B9D2 | ENST00000243578.8 | c.163_164delinsAA | p.Ala55Asn | missense_variant | 3/4 | 1 | NM_030578.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 11, 2017 | This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 3 of the B9D2 mRNA (c.163_164delinsAA), replacing alanine with asparagine at codon 55 of the B9D2 protein (p.Ala55Asn). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and asparagine. This variant is reported as two separate single-nucleotide changes in the ExAC database (c.163G>A and c.164C>A), but the read data shows that the two variants are in cis, recapitulating the variant observed here (c.163_164delinsAA), in 2 individuals. It has not been reported in the literature in individuals with a B9D2-related disease Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at