6-80136272-T-C

Variant names:

• chr6-80136272-T-C
• rs2322633
• NM_183050.4:c.343+7043T>C

Variant summary

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

The NM_183050.4(BCKDHB):​c.343+7043T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 151,946 control chromosomes in the GnomAD database, including 18,634 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 0.49 (18634 hom., cov: 32)
• Consequence: BCKDHB NM_183050.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.654
• Publications: 14 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	NM_183050.4	MANE Select	c.343+7043T>C		intron	N/A	NP_898871.1
	BCKDHB	NM_001424035.1		c.343+7043T>C		intron	N/A	NP_001410964.1
	BCKDHB	NM_000056.5		c.343+7043T>C		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.343+7043T>C		intron	N/A	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.343+7043T>C		intron	N/A	ENSP00000348880.5
	BCKDHB	ENST00000369760.8	TSL:3	c.343+7043T>C		intron	N/A	ENSP00000358775.4

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73998 AN: 151828 Hom.: 18600 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.524

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

GnomAD4 genome AF: 0.488 AC: 74078 AN: 151946 Hom.: 18634 Cov.: 32 AF XY: 0.495 AC XY: 36716 AN XY: 74222

African (AFR) AF: 0.391 AC: 16186 AN: 41432

American (AMR) AF: 0.616 AC: 9392 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1902 AN: 3472

East Asian (EAS) AF: 0.697 AC: 3597 AN: 5164

South Asian (SAS) AF: 0.666 AC: 3211 AN: 4822

European-Finnish (FIN) AF: 0.484 AC: 5106 AN: 10560

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.484 AC: 32892 AN: 67928

Other (OTH) AF: 0.529 AC: 1117 AN: 2110

Alfa AF: 0.485 Hom.: 31673

Bravo AF: 0.490

Asia WGS AF: 0.684 AC: 2378 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.59
PhyloP100		-0.65
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: rs2322633; hg19: chr6-80845989;