rs2223876

Variant names:

• chr6-80334322-G-A
• rs2223876
• NM_183050.4:c.1039-9342G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-80334322-G-A
• chr6-80334322-G-T

Variant summary

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

The NM_183050.4(BCKDHB):​c.1039-9342G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 151,978 control chromosomes in the GnomAD database, including 46,135 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 0.78 (46135 hom., cov: 32)
• Consequence: BCKDHB NM_183050.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 3 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 (AMR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4	c.1039-9342G>A		intron_variant	Intron 9 of 9	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.1039-9342G>A		intron_variant	Intron 9 of 9	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.1039-9342G>A		intron_variant	Intron 9 of 10	1		ENSP00000348880.5

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117866 AN: 151860 Hom.: 46108 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.795

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

GnomAD4 genome AF: 0.776 AC: 117950 AN: 151978 Hom.: 46135 Cov.: 32 AF XY: 0.774 AC XY: 57509 AN XY: 74296

African (AFR) AF: 0.683 AC: 28319 AN: 41440

American (AMR) AF: 0.836 AC: 12772 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2949 AN: 3468

East Asian (EAS) AF: 0.749 AC: 3874 AN: 5172

South Asian (SAS) AF: 0.612 AC: 2951 AN: 4818

European-Finnish (FIN) AF: 0.802 AC: 8484 AN: 10578

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 55932 AN: 67912

Other (OTH) AF: 0.795 AC: 1680 AN: 2114

Alfa AF: 0.788 Hom.: 6160

Bravo AF: 0.778

Asia WGS AF: 0.670 AC: 2319 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.51
PhyloP100		1.1
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: rs2223876; hg19: chr6-81044039;