16-31109233-G-C

Position:

• chr16-31109233-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005881.4(BCKDK):​c.10G>C​(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,364,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1981337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDK	NM_005881.4	c.10G>C	p.Ala4Pro	missense_variant	2/12	ENST00000219794.11	NP_005872.2
BCKDK	NM_001122957.4	c.10G>C	p.Ala4Pro	missense_variant	2/11		NP_001116429.1
BCKDK	NM_001271926.3	c.10G>C	p.Ala4Pro	missense_variant	2/10		NP_001258855.1
BCKDK	XM_017022859.2	c.10G>C	p.Ala4Pro	missense_variant	2/12		XP_016878348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDK	ENST00000219794.11	c.10G>C	p.Ala4Pro	missense_variant	2/12	1	NM_005881.4	ENSP00000219794.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000616 AC: 1 AN: 162406 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88234

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000879 AC: 12 AN: 1364526 Hom.: 0 Cov.: 33 AF XY: 0.00000896 AC XY: 6 AN XY: 669450

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000834 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2020

This variant has not been reported in the literature in individuals with BCKDK-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant is present in population databases (rs775430762, ExAC 0.003%). This sequence change replaces alanine with proline at codon 4 of the BCKDK protein (p.Ala4Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;.;T;.;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N;N;N;N;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.029	D;D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D
Polyphen		0.14	B;.;.;B;.;.;.
Vest4		0.57
MutPred		0.20		Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);Gain of catalytic residue at A4 (P = 0.0262);
MVP		0.65
MPC		0.72
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.89

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: rs775430762; hg19: chr16-31120554;