16-31109416-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005881.4(BCKDK):c.193A>G(p.Lys65Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDK NM_005881.4 missense, splice_region
• Scores: Splicing: ADA: 0.8418
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.62

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDK	NM_005881.4	c.193A>G	p.Lys65Glu	missense_variant, splice_region_variant	2/12	ENST00000219794.11
BCKDK	NM_001122957.4	c.193A>G	p.Lys65Glu	missense_variant, splice_region_variant	2/11
BCKDK	NM_001271926.3	c.193A>G	p.Lys65Glu	missense_variant, splice_region_variant	2/10
BCKDK	XM_017022859.2	c.193A>G	p.Lys65Glu	missense_variant, splice_region_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11	c.193A>G	p.Lys65Glu	missense_variant, splice_region_variant	2/12	1	NM_005881.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Branched-chain keto acid dehydrogenase kinase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N;N;N;D;D
REVEL	Benign	0.29
Sift	Benign	0.11	T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;D;D
Polyphen		0.78	P;.;.;P;.;.
Vest4		0.66
MutPred		0.42		Loss of ubiquitination at K65 (P = 0.0077);Loss of ubiquitination at K65 (P = 0.0077);Loss of ubiquitination at K65 (P = 0.0077);Loss of ubiquitination at K65 (P = 0.0077);Loss of ubiquitination at K65 (P = 0.0077);Loss of ubiquitination at K65 (P = 0.0077);
MVP		0.56
MPC		1.5
ClinPred		0.85	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.47
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: rs1596808163; hg19: chr16-31120737;