Genetic Variant NM_005881.4:c.34G>T (chr16-31109257-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005881.4(BCKDK):c.34G>T(p.Gly12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,550,638 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BCKDK
NM_005881.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.826

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=0.1356279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDK	NM_005881.4 link	c.34G>T	p.Gly12Trp	missense_variant	Exon 2 of 12	ENST00000219794.11	NP_005872.2	O14874-1A0A024QZA9
BCKDK	NM_001122957.4 link	c.34G>T	p.Gly12Trp	missense_variant	Exon 2 of 11		NP_001116429.1	O14874-3
BCKDK	NM_001271926.3 link	c.34G>T	p.Gly12Trp	missense_variant	Exon 2 of 10		NP_001258855.1	O14874-2
BCKDK	XM_017022859.2 link	c.34G>T	p.Gly12Trp	missense_variant	Exon 2 of 12		XP_016878348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDK	ENST00000219794.11 link	c.34G>T	p.Gly12Trp	missense_variant	Exon 2 of 12	1	NM_005881.4	ENSP00000219794.6		O14874-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398464

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690624

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:

0.0000213

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.10

T;.;.;T;.;T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.48

.;T;T;T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

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

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.090

N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.018

D;D;D;D;D;D;D

Sift4G

Benign

0.12

T;D;D;T;D;D;D

Polyphen

0.0

B;.;.;B;.;.;.

Vest4

0.26

MutPred

0.35

Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);

MVP

0.43

MPC

0.65

ClinPred

0.59

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.077

gMVP

0.74

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over