rs146786097

Variant names:

• chr2-218660503-AC-A
• rs146786097
• NM_001079866.2:c.-49-435delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001371446.1(BCS1L):​c.-294delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 170,624 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (47 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: BCS1L NM_001371446.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0410
• 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 -10 ACMG points.

• BP6: Variant 2-218660503-AC-A is Benign according to our data. Variant chr2-218660503-AC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 676726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1887/152312) while in subpopulation AFR AF = 0.0434 (1802/41552). AF 95% confidence interval is 0.0417. There are 47 homozygotes in GnomAd4. There are 884 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR,AD gene

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.-49-435delC		intron	N/A	NP_001073335.1	Q9Y276
	BCS1L	NM_001371446.1		c.-294delC		5_prime_UTR	Exon 1 of 8	NP_001358375.1	A0A024R445
	BCS1L	NM_001374085.1		c.-484delC		5_prime_UTR	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.-49-435delC		intron	N/A	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.-50+286delC		intron	N/A	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.-50+259delC		intron	N/A	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1881 AN: 152194 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.000928 AC: 17 AN: 18312 Hom.: 0 Cov.: 0 AF XY: 0.000946 AC XY: 9 AN XY: 9518

African (AFR) AF: 0.0159 AC: 6 AN: 378

American (AMR) AF: 0.00258 AC: 8 AN: 3098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 218

East Asian (EAS) AF: 0.00 AC: 0 AN: 1444

South Asian (SAS) AF: 0.00 AC: 0 AN: 2406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.000104 AC: 1 AN: 9596

Other (OTH) AF: 0.00256 AC: 2 AN: 782

GnomAD4 genome AF: 0.0124 AC: 1887 AN: 152312 Hom.: 47 Cov.: 32 AF XY: 0.0119 AC XY: 884 AN XY: 74488

African (AFR) AF: 0.0434 AC: 1802 AN: 41552

American (AMR) AF: 0.00418 AC: 64 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0141

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism

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: rs146786097; hg19: chr2-219525226;