rs121908579

Positions:

• chr2-218661090-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001079866.2(BCS1L):​c.103G>C​(p.Gly35Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.11

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-218661090-G-C is Pathogenic according to our data. Variant chr2-218661090-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6172.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCS1L	NM_001079866.2	c.103G>C	p.Gly35Arg	missense_variant	2/8	ENST00000359273.8	NP_001073335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8	c.103G>C	p.Gly35Arg	missense_variant	2/8	1	NM_001079866.2	ENSP00000352219.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bjornstad syndrome with mild mitochondrial complex III deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 22, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D;D;D;D;D;.;D;D;D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;.;D;.;.;.;D;.;.;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;M;M;.;M;M;M;M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.013	D;T;T;D;D;D;D;D;D;D;D;.
Polyphen		0.96	.;.;.;D;D;D;.;D;D;D;D;.
Vest4		0.96, 0.95, 0.96, 0.96
MutPred		0.91		Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);Gain of methylation at G35 (P = 0.0073);
MVP		0.96
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908579; hg19: chr2-219525813;