rs752762669

Variant names:

• chr4-122743421-CACAGATGCA-C
• rs752762669
• NM_152618.3:c.1531_1539delCAGATGCAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PM4 PP5_Very_Strong

The NM_152618.3(BBS12):​c.1531_1539delCAGATGCAA​(p.Gln511_Gln513del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000502 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000941480: Experimental studies have shown that this variant affects BBS12 function (PMID:20498079).; SCV004241180: At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects protein function (Zaghloul_2010).; SCV004107409: Functional studies using zebrafish suggest that this variant is deleterious (Supp. Table 4, Zaghloul et al. 2010. PubMed ID: 20498079).; SCV005325062: Published functional studies in zebrafish suggest a damaging effect (PMID:20498079)".

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: BBS12 NM_152618.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.96
• Publications: 2 publications found

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]

BBS12 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, G2P, Ambry Genetics
• BBS12-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000941480: Experimental studies have shown that this variant affects BBS12 function (PMID: 20498079).; SCV004241180: At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects protein function (Zaghloul_2010).; SCV004107409: Functional studies using zebrafish suggest that this variant is deleterious (Supp. Table 4, Zaghloul et al. 2010. PubMed ID: 20498079).; SCV005325062: Published functional studies in zebrafish suggest a damaging effect (PMID: 20498079)
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_152618.3.
• PP5: Variant 4-122743421-CACAGATGCA-C is Pathogenic according to our data. Variant chr4-122743421-CACAGATGCA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 434492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152618.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	NM_152618.3	MANE Select	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	Exon 3 of 3	NP_001171478.1	Q6ZW61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.1531_1539delCAGATGCAA	p.Gln511_Gln513del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000438273.1	Q6ZW61

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251428 AF XY: 0.0000147

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: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461888 Hom.: 0 AF XY: 0.0000468 AC XY: 34 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1112008

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Bardet-Biedl syndrome 12 (5)
2	-	-	Bardet-Biedl syndrome (2)
1	-	-	BBS12-related disorder (1)
1	-	-	not provided (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs752762669; hg19: chr4-123664576;