chr2-218660284-G-A

Position:

• chr2-218660284-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001079866.2(BCS1L):​c.-50+541G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 152,592 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.056 (333 hom., cov: 32)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: BCS1L NM_001079866.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.215

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 -16 ACMG points.

• BP6: Variant 2-218660284-G-A is Benign according to our data. Variant chr2-218660284-G-A is described in ClinVar as [Benign]. Clinvar id is 673726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCS1L	NM_001079866.2	c.-50+541G>A		intron_variant		ENST00000359273.8	NP_001073335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8	c.-50+541G>A		intron_variant		1	NM_001079866.2	ENSP00000352219	P1

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8471 AN: 152130 Hom.: 332 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0504

GnomAD4 exome AF: 0.0203 AC: 7 AN: 344 Hom.: 0 Cov.: 0 AF XY: 0.0253 AC XY: 5 AN XY: 198

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0557 AC: 8485 AN: 152248 Hom.: 333 Cov.: 32 AF XY: 0.0547 AC XY: 4073 AN XY: 74452

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0437

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.0499

Alfa AF: 0.0434 Hom.: 40

Bravo AF: 0.0585

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

GRACILE syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.67
BranchPoint Hunter		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3806556; hg19: chr2-219525007;