2-218661516-G-T

Variant names:

• chr2-218661516-G-T
• rs386833857
• NM_001079866.2:c.431G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001079866.2(BCS1L):​c.431G>T​(p.Arg144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R144Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.75
• 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), PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, G2P
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, ClinGen
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218661516-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56413.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCS1L	NM_001079866.2	c.431G>T	p.Arg144Leu	missense_variant	Exon 3 of 8	ENST00000359273.8	NP_001073335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8	c.431G>T	p.Arg144Leu	missense_variant	Exon 3 of 8	1	NM_001079866.2	ENSP00000352219.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;.;D;D;D;D;D;D;D;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;.;.;.;.;.;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.8	.;.;.;M;M;M;M;M;M;M;.
PhyloP100		9.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.038	D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.045	D;D;T;D;D;D;D;D;D;D;.
Polyphen		0.037	.;.;.;B;B;B;B;B;B;B;.
Vest4		0.94, 0.94, 0.95, 0.95, 0.95
MutPred		0.84		Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);.;Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);Loss of methylation at K145 (P = 0.0473);
MVP		0.99
MPC		0.94
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.85
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386833857; hg19: chr2-219526239;