rs786204189

chr19-41357947-GCCATGTCC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_030578.4(B9D2):c.156_163del(p.Asp53LeufsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.000013 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: B9D2 NM_030578.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.24

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41357947-GCCATGTCC-G is Pathogenic according to our data. Variant chr19-41357947-GCCATGTCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188273.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B9D2	NM_030578.4	c.156_163del	p.Asp53LeufsTer47	frameshift_variant	3/4	ENST00000243578.8
B9D2	XM_011527349.3	c.156_163del	p.Asp53LeufsTer47	frameshift_variant	3/4
B9D2	XM_011527350.3	c.-4_4del		start_lost, 5_prime_UTR_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B9D2	ENST00000243578.8	c.156_163del	p.Asp53LeufsTer47	frameshift_variant	3/4	1	NM_030578.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461864 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 727232

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000708 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

This sequence change creates a premature translational stop signal (p.Asp53Leufs*47) in the B9D2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the B9D2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with B9D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188273). This variant disrupts a region of the B9D2 protein in which other variant(s) (p.Ser101Arg) have been determined to be pathogenic (PMID: 21763481). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial aplasia of the vermis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2014

This sequence change results in a premature translational stop signal in the last exon of the B9D2 mRNA at codon 100 (p.Asp53Leufs*47). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated B9d2 protein. This sequence change has not been published in the literature and is not present in population databases. Two related individuals with Meckel syndrome were found to be homozygous for the missense mutation, p.Ser101Arg (PMID: 21763481). Functional studies of the p.Ser101Arg change suggest that this missense result in abrogated B9d2 binding with Mks1, likely due to the disruption of the B9 domain. This p.Asp53Leufs*47 change is expected to result in a premature termination codon one position prior to the reported p.Ser101Arg. Therefore it is likely to also disrupt the B9 domain. For these reasons, this sequence change has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204189; hg19: chr19-41863852;