chr4-122742954-G-C

Variant names:

• chr4-122742954-G-C
• rs34296401
• NM_152618.3:c.1062G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152618.3(BBS12):​c.1062G>C​(p.Val354Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,124 control chromosomes in the GnomAD database, including 473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V354V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (129 hom., cov: 33)
  • Exomes 𝑓: 0.018 (344 hom.)
• Consequence: BBS12 NM_152618.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.171
• Publications: 6 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-122742954-G-C is Benign according to our data. Variant chr4-122742954-G-C is described in ClinVar as Benign. ClinVar VariationId is 262668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

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.1062G>C	p.Val354Val	synonymous	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1062G>C	p.Val354Val	synonymous	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.1062G>C	p.Val354Val	synonymous	Exon 2 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.1062G>C	p.Val354Val	synonymous	Exon 3 of 3	ENSP00000438273.1	Q6ZW61

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4531 AN: 152170 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0358

GnomAD2 exomes AF: 0.0167 AC: 4191 AN: 251324 AF XY: 0.0153

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0179 AC: 26140 AN: 1461836 Hom.: 344 Cov.: 32 AF XY: 0.0171 AC XY: 12404 AN XY: 727216

African (AFR) AF: 0.0654 AC: 2188 AN: 33478

American (AMR) AF: 0.0152 AC: 680 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 778 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86250

European-Finnish (FIN) AF: 0.00565 AC: 302 AN: 53418

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.0186 AC: 20706 AN: 1111974

Other (OTH) AF: 0.0217 AC: 1310 AN: 60394

GnomAD4 genome AF: 0.0298 AC: 4535 AN: 152288 Hom.: 129 Cov.: 33 AF XY: 0.0286 AC XY: 2128 AN XY: 74478

African (AFR) AF: 0.0669 AC: 2780 AN: 41546

American (AMR) AF: 0.0230 AC: 352 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1193 AN: 68020

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0136 Hom.: 6

Bravo AF: 0.0333

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Bardet-Biedl syndrome 1 (2)
-	-	2	Bardet-Biedl syndrome 12 (2)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.74
DANN	Benign	0.52
PhyloP100		0.17
Mutation Taster		=100/0	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: rs34296401; hg19: chr4-123664109;