16-31109254-C-G

Variant names:

• chr16-31109254-C-G
• rs764651763
• NM_005881.4:c.31C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005881.4(BCKDK):​c.31C>G​(p.Pro11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,394,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05274895).

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.31C>G	p.Pro11Ala	missense	Exon 2 of 12	NP_005872.2	O14874-1
	BCKDK	NM_001122957.4		c.31C>G	p.Pro11Ala	missense	Exon 2 of 11	NP_001116429.1	O14874-3
	BCKDK	NM_001271926.3		c.31C>G	p.Pro11Ala	missense	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.31C>G	p.Pro11Ala	missense	Exon 2 of 12	ENSP00000219794.6	O14874-1
	BCKDK	ENST00000287507.7	TSL:1	c.31C>G	p.Pro11Ala	missense	Exon 2 of 10	ENSP00000287507.3	O14874-2
	BCKDK	ENST00000394951.5	TSL:5	c.31C>G	p.Pro11Ala	missense	Exon 3 of 13	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000539 AC: 1 AN: 185604 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394018 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 687798

African (AFR) AF: 0.00 AC: 0 AN: 31290

American (AMR) AF: 0.00 AC: 0 AN: 34468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39024

South Asian (SAS) AF: 0.00 AC: 0 AN: 77538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080194

Other (OTH) AF: 0.00 AC: 0 AN: 57262

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.1
DANN	Benign	0.45
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.0020
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.047
Sift	Benign	0.089	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.26		Gain of catalytic residue at P11 (P = 0.021)
MVP		0.20
MPC		0.54
ClinPred		0.027	T
GERP RS		2.5
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.77
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs764651763; hg19: chr16-31120575;