16-31109340-C-G

Position:

• chr16-31109340-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005881.4(BCKDK):​c.117C>G​(p.His39Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05960813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDK	NM_005881.4	c.117C>G	p.His39Gln	missense_variant	2/12	ENST00000219794.11
BCKDK	NM_001122957.4	c.117C>G	p.His39Gln	missense_variant	2/11
BCKDK	NM_001271926.3	c.117C>G	p.His39Gln	missense_variant	2/10
BCKDK	XM_017022859.2	c.117C>G	p.His39Gln	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11	c.117C>G	p.His39Gln	missense_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 16, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with BCKDK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 39 of the BCKDK protein (p.His39Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.4
DANN	Benign	0.81
DEOGEN2	Benign	0.14	T;.;.;T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;.;.;.
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.86	N;N;N;N;D;N;N
REVEL	Benign	0.11
Sift	Benign	0.053	T;T;D;T;D;D;D
Sift4G	Benign	0.17	T;T;T;T;D;T;T
Polyphen		0.013	B;.;.;B;.;.;.
Vest4		0.22
MutPred		0.12		Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);Loss of glycosylation at T37 (P = 0.0493);
MVP		0.26
MPC		0.56
ClinPred		0.095	T
GERP RS		-5.6
Varity_R		0.088
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-31120661;