chr2-218662963-G-GC

Variant names:

• chr2-218662963-G-GC
• rs1057516518
• NM_001079866.2:c.973dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001079866.2(BCS1L):​c.973dupC​(p.Arg325ProfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCS1L NM_001079866.2 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.69
• Publications: 0 publications found

Genes affected

BCS1L (HGNC:1020): (BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone) This gene encodes a homolog of the S. cerevisiae bcs1 protein which is involved in the assembly of complex III of the mitochondrial respiratory chain. The encoded protein does not contain a mitochondrial targeting sequence but experimental studies confirm that it is imported into mitochondria. Mutations in this gene are associated with mitochondrial complex III deficiency and the GRACILE syndrome. Several alternatively spliced transcripts encoding two different isoforms have been described. [provided by RefSeq, Jan 2016]

BCS1L Gene-Disease associations (from GenCC):

• Bjornstad syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial complex III deficiency nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal tubulopathy-encephalopathy-liver failure syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-218662963-G-GC is Pathogenic according to our data. Variant chr2-218662963-G-GC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 370478.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079866.2. 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
	BCS1L	NM_001079866.2	MANE Select	c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 7 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001257342.2		c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 8 of 9	NP_001244271.1	Q9Y276
	BCS1L	NM_001257343.2		c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 8 of 9	NP_001244272.1	A0A024R445

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 7 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 8 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.973dupC	p.Arg325ProfsTer11	frameshift	Exon 8 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	GRACILE syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

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: rs1057516518; hg19: chr2-219527686;