2-218660612-C-T

Variant names:

• chr2-218660612-C-T
• rs3770218
• NM_001079866.2:c.-49-327C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001371446.1(BCS1L):​c.-186C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 238,626 control chromosomes in the GnomAD database, including 35,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19742 hom., cov: 32)
  • Exomes 𝑓: 0.58 (15325 hom.)
• Consequence: BCS1L NM_001371446.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182
• Publications: 13 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 -16 ACMG points.

• BP6: Variant 2-218660612-C-T is Benign according to our data. Variant chr2-218660612-C-T is described in ClinVar as Benign. ClinVar VariationId is 669695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 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.-49-327C>T		intron	N/A	NP_001073335.1	Q9Y276
	BCS1L	NM_001371446.1		c.-186C>T		5_prime_UTR	Exon 1 of 8	NP_001358375.1	A0A024R445
	BCS1L	NM_001374085.1		c.-376C>T		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.-49-327C>T		intron	N/A	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.-49-327C>T		intron	N/A	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.-49-327C>T		intron	N/A	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70944 AN: 151906 Hom.: 19743 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.519

GnomAD4 exome AF: 0.577 AC: 50003 AN: 86602 Hom.: 15325 Cov.: 0 AF XY: 0.587 AC XY: 26077 AN XY: 44388

African (AFR) AF: 0.127 AC: 484 AN: 3804

American (AMR) AF: 0.573 AC: 2587 AN: 4518

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 1388 AN: 2344

East Asian (EAS) AF: 0.827 AC: 4387 AN: 5304

South Asian (SAS) AF: 0.657 AC: 6315 AN: 9612

European-Finnish (FIN) AF: 0.566 AC: 1800 AN: 3180

Middle Eastern (MID) AF: 0.676 AC: 234 AN: 346

European-Non Finnish (NFE) AF: 0.571 AC: 30088 AN: 52692

Other (OTH) AF: 0.566 AC: 2720 AN: 4802

GnomAD4 genome AF: 0.467 AC: 70935 AN: 152024 Hom.: 19742 Cov.: 32 AF XY: 0.475 AC XY: 35284 AN XY: 74326

African (AFR) AF: 0.147 AC: 6101 AN: 41472

American (AMR) AF: 0.554 AC: 8452 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2082 AN: 3470

East Asian (EAS) AF: 0.819 AC: 4236 AN: 5172

South Asian (SAS) AF: 0.674 AC: 3248 AN: 4818

European-Finnish (FIN) AF: 0.573 AC: 6046 AN: 10552

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38933 AN: 67966

Other (OTH) AF: 0.519 AC: 1093 AN: 2104

Alfa AF: 0.508 Hom.: 2655

Bravo AF: 0.449

Asia WGS AF: 0.699 AC: 2429 AN: 3478

ClinVar

ClinVar submissions

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	-0.85
CADD	Benign	9.3
DANN	Benign	0.80
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 23

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

Other links and lift over

dbSNP: rs3770218; hg19: chr2-219525335;