rs116684290

Variant names:

• chr2-218660549-A-G
• rs116684290
• NM_001079866.2:c.-49-390A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371446.1(BCS1L):​c.-249A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 184,144 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (2 hom.)
• Consequence: BCS1L NM_001371446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115
• Publications: 0 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: Orphanet, ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-218660549-A-G is Benign according to our data. Variant chr2-218660549-A-G is described in ClinVar as Benign. ClinVar VariationId is 1239390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	NM_001079866.2	MANE Select	c.-49-390A>G		intron	N/A	NP_001073335.1	Q9Y276
	BCS1L	NM_001371446.1		c.-249A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001358375.1	A0A024R445
	BCS1L	NM_001374085.1		c.-439A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001361014.1	A0A024R445

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.-49-390A>G		intron	N/A	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.-50+331A>G		intron	N/A	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.-50+304A>G		intron	N/A	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4058 AN: 152108 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00345 AC: 110 AN: 31918 Hom.: 2 Cov.: 0 AF XY: 0.00272 AC XY: 45 AN XY: 16516

African (AFR) AF: 0.0800 AC: 87 AN: 1088

American (AMR) AF: 0.00513 AC: 18 AN: 3512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 626

East Asian (EAS) AF: 0.00 AC: 0 AN: 2496

South Asian (SAS) AF: 0.000265 AC: 1 AN: 3776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 78

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 17926

Other (OTH) AF: 0.00259 AC: 4 AN: 1546

GnomAD4 genome AF: 0.0267 AC: 4060 AN: 152226 Hom.: 177 Cov.: 32 AF XY: 0.0259 AC XY: 1926 AN XY: 74426

African (AFR) AF: 0.0930 AC: 3860 AN: 41498

American (AMR) AF: 0.00837 AC: 128 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0327 Hom.: 19

Bravo AF: 0.0305

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs116684290; hg19: chr2-219525272;