NM_001079866.2:c.205C>T

Variant names:

• chr2-218661192-C-T
• rs377025174
• NM_001079866.2:c.205C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_001079866.2(BCS1L):​c.205C>T​(p.Arg69Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,614,050 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: "SCV001205466: Experimental studies have shown that this missense change affects BCS1L function (PMID:31435670)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2
• Conservation: PhyloP100: 5.97
• Publications: 6 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001205466: Experimental studies have shown that this missense change affects BCS1L function (PMID: 31435670).; SCV002768359: "Strong phenotype match for this individual." Additionally, it reduced protein expression, mitochondrial respiratory activity and complex III activity (PMID: 31435670).; SCV003922924: At least one of these publications also reported experimental evidence, and demonstrated a partial loss of function in patient derived cells and in yeast complementation assays (Olahova_2019).
• PP5: Variant 2-218661192-C-T is Pathogenic according to our data. Variant chr2-218661192-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 214160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.205C>T	p.Arg69Cys	missense	Exon 2 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001371453.1		c.-272C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001358382.1
	BCS1L	NM_001371454.1		c.-272C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001358383.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.205C>T	p.Arg69Cys	missense	Exon 2 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.205C>T	p.Arg69Cys	missense	Exon 3 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.205C>T	p.Arg69Cys	missense	Exon 3 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251480 AF XY: 0.0000662

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.000140 AC XY: 102 AN XY: 727248

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74322

African (AFR) AF: 0.0000724 AC: 3 AN: 41434

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	GRACILE syndrome (3)
2	1	-	Mitochondrial complex III deficiency nuclear type 1 (3)
2	-	-	not provided (2)
1	1	-	Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pili torti-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.0
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.014	D
Sift4G	Benign	0.11	T
Polyphen		0.98	D
Vest4		0.48
MVP		0.99
MPC		1.8
ClinPred		0.50	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.50
Mutation Taster		=59/41	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377025174; hg19: chr2-219525915; COSMIC: COSV55309665; COSMIC: COSV55309665;