rs13135445

chr4-122743302-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152618.3(BBS12):c.1410C>T(p.Cys470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,613,942 control chromosomes in the GnomAD database, including 43,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3071 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40357 hom.)
• Consequence: BBS12 NM_152618.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0170

Genes affected

BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-122743302-C-T is Benign according to our data. Variant chr4-122743302-C-T is described in ClinVar as [Benign]. Clinvar id is 166728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122743302-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.017 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1410C>T	p.Cys470=	synonymous_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1410C>T	p.Cys470=	synonymous_variant	3/3
BBS12	XM_011531680.3	c.1410C>T	p.Cys470=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1410C>T	p.Cys470=	synonymous_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1410C>T	p.Cys470=	synonymous_variant	3/3	2		P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28381 AN: 152074 Hom.: 3071 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.181 AC: 45613 AN: 251400 Hom.: 4930 AF XY: 0.186 AC XY: 25210 AN XY: 135880

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.227 AC: 331753 AN: 1461750 Hom.: 40357 Cov.: 35 AF XY: 0.225 AC XY: 163917 AN XY: 727178

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.205

GnomAD4 genome AF: 0.187 AC: 28386 AN: 152192 Hom.: 3071 Cov.: 33 AF XY: 0.181 AC XY: 13459 AN XY: 74406

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.184

Alfa AF: 0.223 Hom.: 3182

Bravo AF: 0.179

Asia WGS AF: 0.0710 AC: 247 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.238

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Bardet-Biedl syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.72
Dann	Benign	0.23

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

Other links and lift over

dbSNP: rs13135445; hg19: chr4-123664457; COSMIC: COSV58561968; COSMIC: COSV58561968;