rs775430762

Variant names:

• chr16-31109233-G-A
• rs775430762
• NM_005881.4:c.10G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-31109233-G-A
• chr16-31109233-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005881.4(BCKDK):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,364,526 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. A4P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11531827).

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.10G>A	p.Ala4Thr	missense	Exon 2 of 12	NP_005872.2	O14874-1
	BCKDK	NM_001122957.4		c.10G>A	p.Ala4Thr	missense	Exon 2 of 11	NP_001116429.1	O14874-3
	BCKDK	NM_001271926.3		c.10G>A	p.Ala4Thr	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.10G>A	p.Ala4Thr	missense	Exon 2 of 12	ENSP00000219794.6	O14874-1
	BCKDK	ENST00000287507.7	TSL:1	c.10G>A	p.Ala4Thr	missense	Exon 2 of 10	ENSP00000287507.3	O14874-2
	BCKDK	ENST00000394951.5	TSL:5	c.10G>A	p.Ala4Thr	missense	Exon 3 of 13	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000366 AC: 5 AN: 1364526 Hom.: 0 Cov.: 33 AF XY: 0.00000448 AC XY: 3 AN XY: 669450

African (AFR) AF: 0.00 AC: 0 AN: 30378

American (AMR) AF: 0.00 AC: 0 AN: 29958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20178

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38748

South Asian (SAS) AF: 0.00 AC: 0 AN: 71914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44484

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5204

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1067570

Other (OTH) AF: 0.00 AC: 0 AN: 56092

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.040
Sift	Benign	0.49	T
Sift4G	Benign	0.15	T
Polyphen		0.0050	B
Vest4		0.18
MutPred		0.12		Gain of phosphorylation at A4 (P = 0.113)
MVP		0.52
MPC		0.54
ClinPred		0.41	T
GERP RS		4.6
PromoterAI		0.088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.80
Mutation Taster		=95/5	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: rs775430762; hg19: chr16-31120554;