2-218663143-T-C

Position:

• chr2-218663143-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001079866.2(BCS1L):​c.1017T>C​(p.Pro339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,614,096 control chromosomes in the GnomAD database, including 8,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3979 hom., cov: 32)
  • Exomes 𝑓: 0.050 (4951 hom.)
• Consequence: BCS1L NM_001079866.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.129

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-218663143-T-C is Benign according to our data. Variant chr2-218663143-T-C is described in ClinVar as [Benign]. Clinvar id is 136505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.129 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCS1L	NM_001079866.2	c.1017T>C	p.Pro339=	synonymous_variant	8/8	ENST00000359273.8	NP_001073335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8	c.1017T>C	p.Pro339=	synonymous_variant	8/8	1	NM_001079866.2	ENSP00000352219	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23109 AN: 152092 Hom.: 3958 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.0717 AC: 18033 AN: 251388 Hom.: 1820 AF XY: 0.0645 AC XY: 8769 AN XY: 135892

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.0417

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0614

GnomAD4 exome AF: 0.0505 AC: 73763 AN: 1461886 Hom.: 4951 Cov.: 33 AF XY: 0.0495 AC XY: 36014 AN XY: 727248

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0494

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.0317

Gnomad4 NFE exome AF: 0.0360

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome AF: 0.152 AC: 23191 AN: 152210 Hom.: 3979 Cov.: 32 AF XY: 0.148 AC XY: 11000 AN XY: 74430

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.0740

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0531

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0848 Hom.: 866

Bravo AF: 0.168

Asia WGS AF: 0.0960 AC: 333 AN: 3478

EpiCase AF: 0.0401

EpiControl AF: 0.0417

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GRACILE syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro339Pro in exon 9 of BCS1L: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 50.45% (667/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs35843327). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex III deficiency nuclear type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pili torti-deafness syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.9
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs35843327; hg19: chr2-219527866; COSMIC: COSV55306933; COSMIC: COSV55306933;