chr16-31110716-G-C

Position:

• chr16-31110716-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005881.4(BCKDK):​c.671G>C​(p.Arg224Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.56

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 16-31110716-G-C is Pathogenic according to our data. Variant chr16-31110716-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 39745.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDK	NM_005881.4	c.671G>C	p.Arg224Pro	missense_variant	8/12	ENST00000219794.11	NP_005872.2
BCKDK	NM_001122957.4	c.671G>C	p.Arg224Pro	missense_variant	8/11		NP_001116429.1
BCKDK	NM_001271926.3	c.671G>C	p.Arg224Pro	missense_variant	8/10		NP_001258855.1
BCKDK	XM_017022859.2	c.671G>C	p.Arg224Pro	missense_variant	8/12		XP_016878348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDK	ENST00000219794.11	c.671G>C	p.Arg224Pro	missense_variant	8/12	1	NM_005881.4	ENSP00000219794.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Branched-chain keto acid dehydrogenase kinase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 19, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L;L;L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;D;D;D;N
REVEL	Uncertain	0.59
Sift	Benign	0.21	T;T;D;T;T
Sift4G	Benign	0.27	T;T;T;T;D
Polyphen		0.81	P;.;.;P;.
Vest4		0.85
MutPred		0.57		Loss of MoRF binding (P = 0.0138);Loss of MoRF binding (P = 0.0138);Loss of MoRF binding (P = 0.0138);Loss of MoRF binding (P = 0.0138);.;
MVP		0.88
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs147210405; hg19: chr16-31122037;