2-218661192-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. R69H) has been classified as Uncertain significance.

• 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
• 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: Uncertain_significance. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 214160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32694036).

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>A	p.Arg69Ser	missense	Exon 2 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001257342.2		c.205C>A	p.Arg69Ser	missense	Exon 3 of 9	NP_001244271.1	Q9Y276
	BCS1L	NM_001257343.2		c.205C>A	p.Arg69Ser	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.205C>A	p.Arg69Ser	missense	Exon 2 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.205C>A	p.Arg69Ser	missense	Exon 3 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.205C>A	p.Arg69Ser	missense	Exon 3 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251480 AF XY: 0.00000736

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 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

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: 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: 0.00 AC: 0 AN: 1112010

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.34
Sift	Benign	0.14	T
Sift4G	Benign	0.77	T
Polyphen		0.021	B
Vest4		0.40
MutPred		0.57		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
Mutation Taster		=53/47	polymorphism

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;