NM_024685.4:c.2119_2120delGT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_024685.4(BBS10):c.2119_2120delGT(p.Val707fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000141 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

BBS10
NM_024685.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.02

Publications

7 publications found

Variant links:

Genes affected

BBS10 (HGNC:26291): (Bardet-Biedl syndrome 10) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by progressive retinal degeneration, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene is likely not a ciliary protein but rather has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins. Inhibition of this protein's expression impairs ciliogenesis in preadipocytes. Mutations in this gene cause Bardet-Biedl syndrome type 10. [provided by RefSeq, Jan 2010]

BBS10 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS10 links:

ENSG00000306428 (HGNC:):

ENSG00000306428 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0244 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PP5

Variant 12-76345864-AAC-A is Pathogenic according to our data. Variant chr12-76345864-AAC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS10	NM_024685.4 link	c.2119_2120delGT	p.Val707fs	frameshift_variant	Exon 2 of 2	ENST00000650064.2	NP_078961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
BBS10	ENST00000650064.2 link	c.2119_2120delGT	p.Val707fs	frameshift_variant	Exon 2 of 2	NM_024685.4	ENSP00000497413.1
ENSG00000306428	ENST00000818399.1 link	n.175-1291_175-1290delCA		intron_variant	Intron 2 of 2
ENSG00000306428	ENST00000818400.1 link	n.202-1291_202-1290delCA		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251218

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

221

AN:

1461572

Hom.:

AF XY:

0.000135

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000192

AC:

214

AN:

1111794

Other (OTH)

AF:

0.000116

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000394

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 10

Pathogenic:5

Jun 01, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 18, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshifting variant in exon 2 of 2 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 17 amino acids of the BBS10 protein. This variant has been previously reported as a compound heterozygous or homozygous change in patients with Bardet-Biedl Syndrome 10 (PMID: 16582908, 25982971, 22773737, 27486776, 20472660). The ClinVar database contains an entry for this variant (Variation ID: 406221). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (17/282614) and thus is presumed to be rare. Based on the available evidence, the c.2119_2120del (p.Val707Ter) variant is classified as Pathogenic. -

Bardet-Biedl syndrome

Pathogenic:3

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val707*) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs775950661, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20472660, 22773737, 25982971, 27486776). ClinVar contains an entry for this variant (Variation ID: 406221). For these reasons, this variant has been classified as Pathogenic. -

Feb 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Val707X (NM_024685.3 c.2119_2120delGT) variant in BBS10 has been previousl y reported in at least one compound heterozygous and one homozygous individual w ith Bardet-Biedl syndrome (BBS) (Stoetzel 2006, Scheidecker 2015, Lindstrand 201 6). This variant has also been reported in ClinVar (Variation ID#406221) as path ogenic. It has been identified in (15/126,508) of European chromosomes by the Ge nome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775 950661). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. This no nsense variant leads to a premature termination codon at position 707, which is predicted to lead to a truncated or absent protein. Biallelic loss of function o f the BBS10 gene has been associated with Bardet-Biedl syndrome (BBS). In summar y, although additional studies are required to fully establish its clinical sign ificance, the p.Val707X variant is likely pathogenic for Bardet-Biedl syndrome ( BBS) in an autosomal recessive manner based on a predicted truncating effect and its biallelic occurrence in individuals with this disease. -

Aug 22, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BBS10 c.2119_2120delGT (p.Val707Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121352 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). This variant has been reported in multiple BBS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:1

Sep 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 21157496, 31293383, 31963381, 16582908, 25982971, 30609409, 22773737, 27659767, 21209035, 27486776, 20472660, 34940782, 35112343) -

Retinal dystrophy

Pathogenic:1

Dec 09, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=60/140

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over