chr6-80229511-G-A

Variant names:

• chr6-80229511-G-A
• rs688867
• NM_183050.4:c.951+26299G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001424035.1(BCKDHB):​c.951+26299G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,018 control chromosomes in the GnomAD database, including 7,934 homozygotes. 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: 𝑓 0.31 (7934 hom., cov: 32)
• Consequence: BCKDHB NM_001424035.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 7 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: ClinGen, G2P, Myriad Women’s Health
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424035.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	NM_183050.4	MANE Select	c.951+26299G>A		intron	N/A	NP_898871.1
	BCKDHB	NM_001424035.1		c.951+26299G>A		intron	N/A	NP_001410964.1
	BCKDHB	NM_000056.5		c.951+26299G>A		intron	N/A	NP_000047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.951+26299G>A		intron	N/A	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.951+26299G>A		intron	N/A	ENSP00000348880.5
	BCKDHB	ENST00000929318.1		c.951+26299G>A		intron	N/A	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47510 AN: 151900 Hom.: 7937 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.313 AC: 47508 AN: 152018 Hom.: 7934 Cov.: 32 AF XY: 0.310 AC XY: 23067 AN XY: 74292

African (AFR) AF: 0.198 AC: 8191 AN: 41466

American (AMR) AF: 0.276 AC: 4220 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1576 AN: 5174

South Asian (SAS) AF: 0.229 AC: 1103 AN: 4822

European-Finnish (FIN) AF: 0.381 AC: 4019 AN: 10538

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26191 AN: 67946

Other (OTH) AF: 0.312 AC: 659 AN: 2114

Alfa AF: 0.356 Hom.: 12978

Bravo AF: 0.306

Asia WGS AF: 0.238 AC: 825 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs688867; hg19: chr6-80939228; COSMIC: COSV57517835;