NM_001079866.2:c.628G>A

Variant names:

• chr2-218661926-G-A
• rs58447305
• NM_001079866.2:c.628G>A

Variant summary

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

The NM_001079866.2(BCS1L):​c.628G>A​(p.Asp210Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,996 control chromosomes in the GnomAD database, including 1,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D210D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (677 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (738 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.36
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial complex III deficiency nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal tubulopathy-encephalopathy-liver failure syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016899705).
• BP6: Variant 2-218661926-G-A is Benign according to our data. Variant chr2-218661926-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 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.628G>A	p.Asp210Asn	missense	Exon 4 of 8	NP_001073335.1	Q9Y276
	BCS1L	NM_001257342.2		c.628G>A	p.Asp210Asn	missense	Exon 5 of 9	NP_001244271.1	Q9Y276
	BCS1L	NM_001257343.2		c.628G>A	p.Asp210Asn	missense	Exon 5 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.628G>A	p.Asp210Asn	missense	Exon 4 of 8	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.628G>A	p.Asp210Asn	missense	Exon 5 of 9	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.628G>A	p.Asp210Asn	missense	Exon 5 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8519 AN: 152074 Hom.: 672 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.0480

GnomAD2 exomes AF: 0.0182 AC: 4579 AN: 251114 AF XY: 0.0146

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.00864 AC: 12634 AN: 1461804 Hom.: 738 Cov.: 33 AF XY: 0.00811 AC XY: 5900 AN XY: 727196

African (AFR) AF: 0.200 AC: 6684 AN: 33474

American (AMR) AF: 0.0156 AC: 697 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 434 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00723 AC: 623 AN: 86226

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53408

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5768

European-Non Finnish (NFE) AF: 0.00254 AC: 2823 AN: 1111994

Other (OTH) AF: 0.0192 AC: 1158 AN: 60396

GnomAD4 genome AF: 0.0562 AC: 8552 AN: 152192 Hom.: 677 Cov.: 32 AF XY: 0.0536 AC XY: 3989 AN XY: 74418

African (AFR) AF: 0.185 AC: 7671 AN: 41490

American (AMR) AF: 0.0276 AC: 422 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 68018

Other (OTH) AF: 0.0480 AC: 101 AN: 2106

Alfa AF: 0.0203 Hom.: 524

Bravo AF: 0.0641

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.182 AC: 803

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.0214 AC: 2603

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00563

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.54	N
PhyloP100		2.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.73	N
REVEL	Uncertain	0.33
Sift	Benign	0.63	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	B
Vest4		0.12
MPC		0.59
ClinPred		0.013	T
GERP RS		4.8
PromoterAI		-0.045	Neutral
Varity_R		0.11
gMVP		0.54
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: rs58447305; hg19: chr2-219526649;