2-218662989-C-T

Variant names:

• chr2-218662989-C-T
• rs33946522
• NM_001079866.2:c.996C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3 BP6_Very_Strong BP7 BA1

The NM_001079866.2(BCS1L):​c.996C>T​(p.Asn332Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,760 control chromosomes in the GnomAD database, including 1,640 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (330 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1310 hom.)
• Consequence: BCS1L NM_001079866.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.15
• Publications: 10 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 -16 ACMG points.

• PP3: REVEL computational evidence supports a deleterious effect, 0.666
• BP6: Variant 2-218662989-C-T is Benign according to our data. Variant chr2-218662989-C-T is described in ClinVar as Benign. ClinVar VariationId is 136503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079866.2. 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.996C>T	p.Asn332Asn	synonymous	Exon 7 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001257342.2		c.996C>T	p.Asn332Asn	synonymous	Exon 8 of 9	NP_001244271.1	Q9Y276
	BCS1L	NM_001257343.2		c.996C>T	p.Asn332Asn	synonymous	Exon 8 of 9	NP_001244272.1	A0A024R445

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.996C>T	p.Asn332Asn	synonymous	Exon 7 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.996C>T	p.Asn332Asn	synonymous	Exon 8 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.996C>T	p.Asn332Asn	synonymous	Exon 8 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.0555 AC: 8430 AN: 151816 Hom.: 329 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: 0.0428

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0504

GnomAD2 exomes AF: 0.0435 AC: 10939 AN: 251478 AF XY: 0.0426

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0376 AC: 55013 AN: 1461826 Hom.: 1310 Cov.: 33 AF XY: 0.0378 AC XY: 27485 AN XY: 727218

African (AFR) AF: 0.107 AC: 3588 AN: 33480

American (AMR) AF: 0.0219 AC: 978 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 856 AN: 26136

East Asian (EAS) AF: 0.113 AC: 4468 AN: 39700

South Asian (SAS) AF: 0.0425 AC: 3670 AN: 86256

European-Finnish (FIN) AF: 0.0314 AC: 1678 AN: 53410

Middle Eastern (MID) AF: 0.0302 AC: 174 AN: 5768

European-Non Finnish (NFE) AF: 0.0333 AC: 37032 AN: 1111958

Other (OTH) AF: 0.0425 AC: 2569 AN: 60394

GnomAD4 genome AF: 0.0556 AC: 8444 AN: 151934 Hom.: 330 Cov.: 32 AF XY: 0.0545 AC XY: 4047 AN XY: 74258

African (AFR) AF: 0.104 AC: 4304 AN: 41376

American (AMR) AF: 0.0311 AC: 475 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3468

East Asian (EAS) AF: 0.119 AC: 614 AN: 5150

South Asian (SAS) AF: 0.0428 AC: 205 AN: 4790

European-Finnish (FIN) AF: 0.0273 AC: 289 AN: 10574

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2300 AN: 67990

Other (OTH) AF: 0.0499 AC: 105 AN: 2106

Alfa AF: 0.0423 Hom.: 144

Bravo AF: 0.0585

Asia WGS AF: 0.0700 AC: 241 AN: 3478

EpiCase AF: 0.0340

EpiControl AF: 0.0357

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	GRACILE syndrome (3)
-	-	2	Mitochondrial complex III deficiency nuclear type 1 (2)
-	-	2	not specified (2)
-	-	1	Leigh syndrome (1)
-	-	1	Pili torti-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.1
DANN	Benign	0.76
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs33946522; hg19: chr2-219527712; COSMIC: COSV55306477; COSMIC: COSV55306477;