6-80106710-C-G

Variant names:

• chr6-80106710-C-G
• rs534975518
• NM_183050.4:c.17C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_183050.4(BCKDHB):​c.17C>G​(p.Ala6Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318

Genes affected

BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4	c.17C>G	p.Ala6Gly	missense_variant	Exon 1 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.17C>G	p.Ala6Gly	missense_variant	Exon 1 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.17C>G	p.Ala6Gly	missense_variant	Exon 1 of 11	1		ENSP00000348880.5
BCKDHB	ENST00000369760.8	c.17C>G	p.Ala6Gly	missense_variant	Exon 1 of 6	3		ENSP00000358775.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.24	.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.70	T;.;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.84	L;L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.043	D;T;T
Polyphen		0.36	.;B;B
Vest4		0.27
MutPred		0.36		Gain of catalytic residue at A6 (P = 0.0137);Gain of catalytic residue at A6 (P = 0.0137);Gain of catalytic residue at A6 (P = 0.0137);
MVP		0.92
MPC		0.20
ClinPred		0.14	T
GERP RS		-2.4
Varity_R		0.081
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -27

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

Publications

LitVar

Other links and lift over

dbSNP: rs534975518; hg19: chr6-80816427;