chr16-31109416-A-G

Variant names:

• chr16-31109416-A-G
• rs1596808163
• NM_005881.4:c.193A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005881.4(BCKDK):​c.193A>G​(p.Lys65Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDK NM_005881.4 missense, splice_region
• Scores: Splicing: ADA: 0.8418
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.62
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• branched-chain keto acid dehydrogenase kinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005881.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	NM_005881.4	MANE Select	c.193A>G	p.Lys65Glu	missense splice_region	Exon 2 of 12	NP_005872.2	O14874-1
	BCKDK	NM_001122957.4		c.193A>G	p.Lys65Glu	missense splice_region	Exon 2 of 11	NP_001116429.1	O14874-3
	BCKDK	NM_001271926.3		c.193A>G	p.Lys65Glu	missense splice_region	Exon 2 of 10	NP_001258855.1	O14874-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	ENST00000219794.11	TSL:1 MANE Select	c.193A>G	p.Lys65Glu	missense splice_region	Exon 2 of 12	ENSP00000219794.6	O14874-1
	BCKDK	ENST00000287507.7	TSL:1	c.193A>G	p.Lys65Glu	missense splice_region	Exon 2 of 10	ENSP00000287507.3	O14874-2
	BCKDK	ENST00000394951.5	TSL:5	c.193A>G	p.Lys65Glu	missense splice_region	Exon 3 of 13	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Branched-chain keto acid dehydrogenase kinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.78	P
Vest4		0.66
MutPred		0.42		Loss of ubiquitination at K65 (P = 0.0077)
MVP		0.56
MPC		1.5
ClinPred		0.85	D
GERP RS		5.5
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.47
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

Other links and lift over

dbSNP: rs1596808163; hg19: chr16-31120737;