6-80106710-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_183050.4(BCKDHB):​c.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,551,508 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -15 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007717788).
• BP6: Variant 6-80106710-C-T is Benign according to our data. Variant chr6-80106710-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 771663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>T	p.Ala6Val	missense	Exon 1 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.17C>T	p.Ala6Val	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>T	p.Ala6Val	missense	Exon 1 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.17C>T	p.Ala6Val	missense	Exon 1 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000547 AC: 81 AN: 148214 AF XY: 0.000740

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: 0.0000373

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.000228 AC: 319 AN: 1399176 Hom.: 2 Cov.: 32 AF XY: 0.000330 AC XY: 228 AN XY: 690510

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 36042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35928

South Asian (SAS) AF: 0.00259 AC: 207 AN: 79774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 0.0000926 AC: 100 AN: 1080230

Other (OTH) AF: 0.000207 AC: 12 AN: 57896

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000420 AC: 44

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BCKDHB-related disorder (1)
-	-	1	Maple syrup urine disease (1)
-	-	1	Maple syrup urine disease type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.32
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.15
Sift	Benign	0.058	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0040	B
Vest4		0.27
MutPred		0.37		Loss of helix (P = 0.0237)
MVP		0.84
MPC		0.20
ClinPred		0.074	T
GERP RS		-2.4
PromoterAI		0.021	Neutral
Varity_R		0.039
gMVP		0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs534975518; hg19: chr6-80816427;