16-31109261-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_005881.4(BCKDK):c.38G>C(p.Gly13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,404,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05123493).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000192 (27/1404756) while in subpopulation SAS AF= 0.000325 (26/80034). AF 95% confidence interval is 0.000227. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDK	NM_005881.4	c.38G>C	p.Gly13Ala	missense_variant	2/12	ENST00000219794.11
BCKDK	NM_001122957.4	c.38G>C	p.Gly13Ala	missense_variant	2/11
BCKDK	NM_001271926.3	c.38G>C	p.Gly13Ala	missense_variant	2/10
BCKDK	XM_017022859.2	c.38G>C	p.Gly13Ala	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11	c.38G>C	p.Gly13Ala	missense_variant	2/12	1	NM_005881.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000516 AC: 10 AN: 193926 Hom.: 0 AF XY: 0.0000837 AC XY: 9 AN XY: 107566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 27 AN: 1404756 Hom.: 0 Cov.: 33 AF XY: 0.0000274 AC XY: 19 AN XY: 694444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000749 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	11
Dann	Benign	0.69
DEOGEN2	Benign	0.095	T;.;.;T;.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.40	N
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.051	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N;N
REVEL	Benign	0.099
Sift	Benign	0.16	T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.;.
Vest4		0.13
MutPred		0.094		Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);Gain of methylation at R18 (P = 0.1103);
MVP		0.44
MPC		0.60
ClinPred		0.041	T
GERP RS		3.1
Varity_R		0.14
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs748666025; hg19: chr16-31120582;