rs377025174

chr2-218661192-C-Achr2-218661192-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001079866.2(BCS1L):c.205C>A(p.Arg69Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218661192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214160.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=4, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32694036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCS1L	NM_001079866.2	c.205C>A	p.Arg69Ser	missense_variant	2/8	ENST00000359273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCS1L	ENST00000359273.8	c.205C>A	p.Arg69Ser	missense_variant	2/8	1	NM_001079866.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.060
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;.;D;.;.;.;D;.;.;.;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.021	.;.;.;B;B;B;.;B;B;B;B;.
Vest4		0.40, 0.41, 0.40, 0.37, 0.37
MutPred		0.57		Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);
MVP		0.99
MPC		0.79
ClinPred		0.42	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.45

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: rs377025174; hg19: chr2-219525915;