chr6-80106710-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318
• Publications: 0 publications found

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]

BCKDHB Gene-Disease associations (from GenCC):

• maple syrup urine disease type 1B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health, ClinGen
• maple syrup urine disease

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• classic maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermittent maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thiamine-responsive maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.17637 (below the threshold of 3.09). Trascript score misZ: -0.0026186 (below the threshold of 3.09). GenCC associations: The gene is linked to classic maple syrup urine disease, thiamine-responsive maple syrup urine disease, intermittent maple syrup urine disease, intermediate maple syrup urine disease, maple syrup urine disease type 1B, maple syrup urine disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183050.4. 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
	BCKDHB	NM_183050.4	MANE Select	c.17C>G	p.Ala6Gly	missense	Exon 1 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.17C>G	p.Ala6Gly	missense	Exon 1 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.17C>G	p.Ala6Gly	missense	Exon 1 of 11	NP_000047.1	A0A140VKB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.17C>G	p.Ala6Gly	missense	Exon 1 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.17C>G	p.Ala6Gly	missense	Exon 1 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.17C>G	p.Ala6Gly	missense	Exon 1 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.32
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.043	D
Polyphen		0.36	B
Vest4		0.27
MutPred		0.36		Gain of catalytic residue at A6 (P = 0.0137)
MVP		0.92
MPC		0.20
ClinPred		0.14	T
GERP RS		-2.4
PromoterAI		-0.15	Neutral
Varity_R		0.081
gMVP		0.52
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs534975518; hg19: chr6-80816427;