19-41354744-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_030578.4(B9D2):c.484G>T(p.Gly162Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,004 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 2 hom. )

Consequence

B9D2
NM_030578.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.0210

Variant links:

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]

B9D2 links:

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]

TMEM91 links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27533376).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000054 (79/1461694) while in subpopulation AFR AF= 0.00102 (34/33480). AF 95% confidence interval is 0.000746. There are 2 homozygotes in gnomad4_exome. There are 44 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B9D2	NM_030578.4 link	c.484G>T	p.Gly162Cys	missense_variant	Exon 4 of 4	ENST00000243578.8	NP_085055.2	Q9BPU9
B9D2	XM_011527349.3 link	c.484G>T	p.Gly162Cys	missense_variant	Exon 4 of 4		XP_011525651.1	Q9BPU9
B9D2	XM_011527350.3 link	c.325G>T	p.Gly109Cys	missense_variant	Exon 3 of 3		XP_011525652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B9D2	ENST00000243578.8 link	c.484G>T	p.Gly162Cys	missense_variant	Exon 4 of 4	1	NM_030578.4	ENSP00000243578.2		Q9BPU9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250866

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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

Bravo

AF:

0.0000642

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

May 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: B9D2 c.484G>T (p.Gly162Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250866 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in B9D2 causing Joubert Syndrome And Related Disorders (6.4e-05 vs 0.0004), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.484G>T in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aug 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.484G>T (p.G162C) alteration is located in exon 4 (coding exon 3) of the B9D2 gene. This alteration results from a G to T substitution at nucleotide position 484, causing the glycine (G) at amino acid position 162 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Jun 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 162 of the B9D2 protein (p.Gly162Cys). This variant is present in population databases (rs760322583, gnomAD 0.02%). 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: 1341710). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Feb 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Meckel syndrome, type 10

Uncertain:1

Jun 26, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous c.484G>T (p.Gly162Cys) variant identified in the B9D2 gene substitutes a moderately conserved Glycine for Cystine at amino acid 162/176 (exon 4/4). This variant is found with low frequency in gnomAD(v3.0) (3 heterozygotes, 0 homozygotes; allele frequency:2.09e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the effect of this variant, as it is predicted both Deleterious (Provean; score:-3.31) and Tolerated (SIFT; score:0.124) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:329340) and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the homozygous c.484G>T (p.Gly162Cys) variant identified in the B9D2 gene is reported here as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.9

DANN

Benign

0.94

DEOGEN2

Benign

0.26

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.14

Sift

Benign

0.12

Sift4G

Benign

0.13

Polyphen

0.0070

Vest4

0.24

MutPred

0.60

Loss of helix (P = 0.0558);

MVP

0.17

MPC

0.26

ClinPred

0.046

GERP RS

-0.68

Varity_R

0.41

gMVP

0.66

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over