2-218662604-G-T

Variant names:

• chr2-218662604-G-T
• rs1193854555
• NM_001079866.2:c.814G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001079866.2(BCS1L):​c.814G>T​(p.Val272Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V272M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001079866.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34870172).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	NM_001079866.2	MANE Select	c.814G>T	p.Val272Leu	missense	Exon 6 of 8	NP_001073335.1
	BCS1L	NM_001257342.2		c.814G>T	p.Val272Leu	missense	Exon 7 of 9	NP_001244271.1
	BCS1L	NM_001257343.2		c.814G>T	p.Val272Leu	missense	Exon 7 of 9	NP_001244272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.814G>T	p.Val272Leu	missense	Exon 6 of 8	ENSP00000352219.3
	BCS1L	ENST00000392109.5	TSL:1	c.814G>T	p.Val272Leu	missense	Exon 7 of 9	ENSP00000375957.1
	BCS1L	ENST00000392111.7	TSL:1	c.814G>T	p.Val272Leu	missense	Exon 7 of 9	ENSP00000375959.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.016
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.40	N
PhyloP100		7.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.46	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.39
MutPred		0.34		Gain of disorder (P = 0.0977)
MVP		0.89
MPC		0.60
ClinPred		0.43	T
GERP RS		5.2
PromoterAI		0.012	Neutral
Varity_R		0.44
gMVP		0.74
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1193854555; hg19: chr2-219527327;