Genetic Variant BCKDK:c.-638C>T (chr16-31106092-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000394951.5(BCKDK):c.-638C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,168 control chromosomes in the GnomAD database, including 9,414 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 9413 hom., cov: 32)

Exomes 𝑓: 0.37 ( 1 hom. )

Consequence

BCKDK
ENST00000394951.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.384

Publications

35 publications found

Variant links:

Genes affected

BCKDK (HGNC:16902): (branched chain keto acid dehydrogenase kinase) The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

BCKDK Gene-Disease associations (from GenCC):

branched-chain keto acid dehydrogenase kinase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

BCKDK links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394951.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	ENST00000394951.5	TSL:5	c.-638C>T		upstream_gene	N/A	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45970

AN:

152022

Hom.:

9412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0715

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.892

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.390

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.370

GnomAD4 exome

AF:

0.367

AC:

AN:

Hom.:

Cov.:

AF XY:

0.385

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.346

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.302

AC:

45970

AN:

152138

Hom.:

9413

Cov.:

AF XY:

0.305

AC XY:

22716

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0713

AC:

2961

AN:

41518

American (AMR)

AF:

0.371

AC:

5670

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1722

AN:

3472

East Asian (EAS)

AF:

0.892

AC:

4611

AN:

5168

South Asian (SAS)

AF:

0.176

AC:

849

AN:

4828

European-Finnish (FIN)

AF:

0.390

AC:

4117

AN:

10566

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.364

AC:

24712

AN:

67980

Other (OTH)

AF:

0.368

AC:

778

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1439

2877

4316

5754

7193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.363

Hom.:

4237

Bravo

AF:

0.304

Asia WGS

AF:

0.455

AC:

1587

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

6.1

(source)

DANN

Benign

0.77

PhyloP100

0.38

PromoterAI

0.064

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over