2-218662661-C-T

Position:

chr2-218662661-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001079866.2(BCS1L):c.871C>T(p.Arg291Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

BCS1L
NM_001079866.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 2.54

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-218662661-C-T is Pathogenic according to our data. Variant chr2-218662661-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214162.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=5, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCS1L	NM_001079866.2 linkuse as main transcript	c.871C>T	p.Arg291Ter	stop_gained	6/8	ENST00000359273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCS1L	ENST00000359273.8 linkuse as main transcript	c.871C>T	p.Arg291Ter	stop_gained	6/8	1	NM_001079866.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250748

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pili torti-deafness syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2022	Variant summary: BCS1L c.871C>T (p.Arg291X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250748 control chromosomes (gnomAD). c.871C>T has been reported in the literature in a compound heterozygote individual affected with Bjornstad syndrome (Hinson_2007). The authors of this study also reported experimental evidence evaluating an impact on protein function, demonstrating in a yeast complementation assay that the mutant protein failed to rescue growth on a medium that requires an active respiratory-chain. They also showed decreased electron-transport activities with increased production of reactive oxygen species in lymphocytes acquired from patients with Bjornstad syndrome and complex III deficiency (however, no patient specific data were provided, Hinson_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change creates a premature termination codon at position 291 in exon 7 (of 9) of BCS1L, p.(Arg291*). It is expected to result in an absent or disrupted protein product in a gene where loss of function is an established mechanism of disease. The variant is present in a large population cohort at a frequency of 0.003%, which is consistent with a recessive condition (rs201454788, 8/282,138 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second allele in a case diagnosed with Bjornstad syndrome (PMID: 17314340). Additionally, the variant demonstrates attenuated growth in a yeast complementation assay (PMID: 17314340). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PS3_Supporting. -

GRACILE syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in mitochondrial dysfunction with reduced electron transport chain activity (Hinson et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 29704315, 25914718, 17314340) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change creates a premature translational stop signal (p.Arg291*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs201454788, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Bjornstad syndrome (PMID: 17314340). ClinVar contains an entry for this variant (Variation ID: 214162). For these reasons, this variant has been classified as Pathogenic. -

BCS1L-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The BCS1L c.871C>T (p.Arg291Ter) variant is a stop-gained variant. The p.Arg291Ter variant has been reported in one study in which it is found in a compound heterozygous state with a missense variant in one individual with Bjornstad syndrome (Hinson et al. 2007). The p.Arg291Ter variant was absent from 300 control chromosomes and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional complementation studies in yeast showed that the variant failed to support growth on media that require respiratory-chain metabolism (Hinson et al. 2007). The amount of superoxide produced by complex III activity was reduced by 61% in mitochondria in individuals with Bjornstad syndrome while complex I-dependent production of reactive oxygen species was increased by 30%. Due to the potential impact of stop-gained variants and the supporting evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

Vest4

0.98

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over