chr2-218661911-G-A

Position:

chr2-218661911-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001079866.2(BCS1L):c.613G>A(p.Val205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,120 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V205V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 67 hom. )

Consequence

BCS1L
NM_001079866.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 2.61

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003763765).

BP6

Variant 2-218661911-G-A is Benign according to our data. Variant chr2-218661911-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr2-218661911-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00297 (452/152274) while in subpopulation AMR AF= 0.0281 (429/15292). AF 95% confidence interval is 0.0259. There are 8 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCS1L	NM_001079866.2 linkuse as main transcript	c.613G>A	p.Val205Ile	missense_variant	4/8	ENST00000359273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCS1L	ENST00000359273.8 linkuse as main transcript	c.613G>A	p.Val205Ile	missense_variant	4/8	1	NM_001079866.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

456

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00756

AC:

1900

AN:

251326

Hom.:

AF XY:

0.00562

AC XY:

764

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.0535

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00162

AC:

2364

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

986

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00297

AC:

452

AN:

152274

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

241

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.00620

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00549

AC:

667

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Val205Ile in exon 5 of BCS1L: This variant is not expected to have clinical si gnificance because it has been identified in 5.64% (644/11418) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148278887). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2014	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. -

GRACILE syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

BCS1L-related disorder

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 25, 2019	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Mitochondrial complex III deficiency nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Leigh syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Benign

9.8

DANN

Benign

0.92

DEOGEN2

Benign

0.0070

T;T;.;T;T;T;T;T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.37

.;T;T;.;.;.;.;.;.;T

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.82

.;.;.;L;L;L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.48

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.27

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T;T;T;T;T

Polyphen

0.0020

.;.;.;B;B;B;B;B;B;B

Vest4

0.11, 0.11, 0.15, 0.15, 0.15

MVP

0.76

MPC

0.49

ClinPred

0.0052

GERP RS

-0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

gMVP

0.40

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

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