rs2298806

Variant names:

• chr11-66514624-G-A
• rs2298806
• NM_024649.5:c.378G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_024649.5(BBS1):​c.378G>A​(p.Leu126Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,210 control chromosomes in the GnomAD database, including 45,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3877 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42057 hom.)
• Consequence: BBS1 NM_024649.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.14
• Publications: 31 publications found

Genes affected

BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

BBS1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health, 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

ENSG00000256349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.137).
• BP6: Variant 11-66514624-G-A is Benign according to our data. Variant chr11-66514624-G-A is described in ClinVar as Benign. ClinVar VariationId is 261750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS1	NM_024649.5	c.378G>A	p.Leu126Leu	synonymous_variant	Exon 4 of 17	ENST00000318312.12	NP_078925.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12	c.378G>A	p.Leu126Leu	synonymous_variant	Exon 4 of 17	1	NM_024649.5	ENSP00000317469.7
ENSG00000256349	ENST00000419755.3	c.489G>A	p.Leu163Leu	synonymous_variant	Exon 4 of 17	2		ENSP00000398526.3

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32259 AN: 151952 Hom.: 3870 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.224 AC: 56195 AN: 250730 AF XY: 0.227

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.235 AC: 344006 AN: 1461140 Hom.: 42057 Cov.: 35 AF XY: 0.236 AC XY: 171356 AN XY: 726920

African (AFR) AF: 0.126 AC: 4208 AN: 33480

American (AMR) AF: 0.144 AC: 6421 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4382 AN: 26134

East Asian (EAS) AF: 0.261 AC: 10358 AN: 39698

South Asian (SAS) AF: 0.215 AC: 18517 AN: 86254

European-Finnish (FIN) AF: 0.372 AC: 19659 AN: 52810

Middle Eastern (MID) AF: 0.132 AC: 761 AN: 5768

European-Non Finnish (NFE) AF: 0.240 AC: 266365 AN: 1111896

Other (OTH) AF: 0.221 AC: 13335 AN: 60376

GnomAD4 genome AF: 0.212 AC: 32278 AN: 152070 Hom.: 3877 Cov.: 32 AF XY: 0.217 AC XY: 16144 AN XY: 74338

African (AFR) AF: 0.135 AC: 5613 AN: 41490

American (AMR) AF: 0.170 AC: 2600 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 522 AN: 3468

East Asian (EAS) AF: 0.268 AC: 1383 AN: 5160

South Asian (SAS) AF: 0.202 AC: 976 AN: 4824

European-Finnish (FIN) AF: 0.387 AC: 4083 AN: 10554

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16457 AN: 67974

Other (OTH) AF: 0.176 AC: 372 AN: 2112

Alfa AF: 0.219 Hom.: 7199

Bravo AF: 0.191

Asia WGS AF: 0.239 AC: 831 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.228

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:6

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 15, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BBS1 c.378G>A (p.Leu126Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant along with 5/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 27024/121032 control chromosomes (3285 homozygotes) at a frequency of 0.2232798, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic BBS1 variant (0.0009449), suggesting this variant is likely a benign polymorphism. A clinical diagnostic laboratory and at least one publication classified this variant as benign. Taken together, this variant is classified as benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Bardet-Biedl syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.70
PhyloP100		1.1
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2298806; hg19: chr11-66282095; COSMIC: COSV59147579; COSMIC: COSV59147579;