rs140812286

Variant names:

• chr2-218661204-C-G
• rs140812286
• NM_001079866.2:c.217C>G
• BCS1L p.Arg73Gly

Your query was ambiguous. Multiple possible variants found:

• chr2-218661204-C-G
• chr2-218661204-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001079866.2(BCS1L):​c.217C>G​(p.Arg73Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 11 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001079866.2

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.217C>G	p.Arg73Gly	missense	Exon 2 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001257342.2		c.217C>G	p.Arg73Gly	missense	Exon 3 of 9	NP_001244271.1	Q9Y276
	BCS1L	NM_001257343.2		c.217C>G	p.Arg73Gly	missense	Exon 3 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.217C>G	p.Arg73Gly	missense	Exon 2 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.217C>G	p.Arg73Gly	missense	Exon 3 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.217C>G	p.Arg73Gly	missense	Exon 3 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.032	D
Varity_R		0.60
gMVP		0.57
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140812286;

hg19: chr2-219525927;