16-31109233-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

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 links:

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ACMG classification

Classification made for transcript

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
BCKDK	NM_005881.4 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	2/12	ENST00000219794.11
BCKDK	NM_001122957.4 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	2/11
BCKDK	NM_001271926.3 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	2/10
BCKDK	XM_017022859.2 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	2/12	1	NM_005881.4	P1	O14874-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000616

AC:

AN:

162406

Hom.:

AF XY:

0.0000113

AC XY:

AN XY:

88234

show subpopulations

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:

AN:

1364526

Hom.:

Cov.:

AF XY:

0.00000896

AC XY:

AN XY:

669450

show subpopulations

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.:

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Branched-chain keto acid dehydrogenase kinase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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

BayesDel_noAF

Benign

-0.27

Cadd

Benign

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

M_CAP

Benign

0.026

MetaRNN

Benign

0.20

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;N;N;N;.;.;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Uncertain

0.71

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over