chr6-80106626-CGGGTGCTCCGCCCTCCCCGCAGGCGGCGTGCGGCTGCATAGCCTGAGAATCCCGGTGGTGAGCGGGGATGGCGGTTGTAGCGGCGGCTGCCGGCTGGCTACTCAGGCTCAGGGCGGCAGGGGCTGAGGGGCACTGGCGTCGGCTTCCTGGCGCGGGGCTGGCGCGGGGCTTTTTGCACCCCGCCGCGACTGTCGAGGATGCGGCCCAGAGGCGGCAGGTGGCTCATTTTACTTTCCAGCCAGATCCGGAGCCCCGGGAGTACG-C

Variant names:

• chr6-80106626-CGGGTGCTCCGCCCTCCCCGCAGGCGGCGTGCGGCTGCATAGCCTGAGAATCCCGGTGGTGAGCGGGGATGGCGGTTGTAGCGGCGGCTGCCGGCTGGCTACTCAGGCTCAGGGCGGCAGGGGCTGAGGGGCACTGGCGTCGGCTTCCTGGCGCGGGGCTGGCGCGGGGCTTTTTGCACCCCGCCGCGACTGTCGAGGATGCGGCCCAGAGGCGGCAGGTGGCTCATTTTACTTTCCAGCCAGATCCGGAGCCCCGGGAGTACG-C
• rs1554180622
• ENST00000320393.9:c.-67_196del

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The ENST00000320393.9(BCKDHB):​c.-67_196del variant causes a 5 prime UTR truncation, exon loss change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB ENST00000320393.9 5_prime_UTR_truncation, exon_loss
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.810
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 6-80106626-CGGGTGCTCCGCCCTCCCCGCAGGCGGCGTGCGGCTGCATAGCCTGAGAATCCCGGTGGTGAGCGGGGATGGCGGTTGTAGCGGCGGCTGCCGGCTGGCTACTCAGGCTCAGGGCGGCAGGGGCTGAGGGGCACTGGCGTCGGCTTCCTGGCGCGGGGCTGGCGCGGGGCTTTTTGCACCCCGCCGCGACTGTCGAGGATGCGGCCCAGAGGCGGCAGGTGGCTCATTTTACTTTCCAGCCAGATCCGGAGCCCCGGGAGTACG-C is Pathogenic according to our data. Variant chr6-80106626-CGGGTGCTCCGCCCTCCCCGCAGGCGGCGTGCGGCTGCATAGCCTGAGAATCCCGGTGGTGAGCGGGGATGGCGGTTGTAGCGGCGGCTGCCGGCTGGCTACTCAGGCTCAGGGCGGCAGGGGCTGAGGGGCACTGGCGTCGGCTTCCTGGCGCGGGGCTGGCGCGGGGCTTTTTGCACCCCGCCGCGACTGTCGAGGATGCGGCCCAGAGGCGGCAGGTGGCTCATTTTACTTTCCAGCCAGATCCGGAGCCCCGGGAGTACG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224058.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000320393.9. 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.-66_196+1del		exon_loss splice_region	Exon 1 of 10	NP_898871.1
	BCKDHB	NM_183050.4	MANE Select	c.-66_196+1del		splice_donor 5_prime_UTR_truncation exon_loss intron	Exon 1 of 10	NP_898871.1
	BCKDHB	NM_001424035.1		c.-66_196+1del		exon_loss splice_region	Exon 1 of 10	NP_001410964.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.-67_196del		5_prime_UTR_truncation exon_loss	Exon 1 of 10	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.-67_196del		5_prime_UTR_truncation exon_loss	Exon 1 of 11	ENSP00000348880.5
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.-67_196del		exon_loss splice_region	Exon 1 of 10	ENSP00000318351.5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Pathogenic:1

Jan 01, 2014

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81

Splicing

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

Other links and lift over

dbSNP: rs1554180622; hg19: chr6-80816343;