chr6-80106698-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_183050.4(BCKDHB):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,555,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.52
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BCKDHBNM_183050.4 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/10 ENST00000320393.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BCKDHBENST00000320393.9 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/101 NM_183050.4 P1P21953-1
BCKDHBENST00000356489.9 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/111 P1P21953-1
BCKDHBENST00000369760.8 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/63 P21953-2

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000434
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000257
AC:
4
AN:
155356
Hom.:
0
AF XY:
0.0000240
AC XY:
2
AN XY:
83446
show subpopulations
Gnomad AFR exome
AF:
0.000504
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
24
AN:
1403258
Hom.:
0
Cov.:
32
AF XY:
0.0000101
AC XY:
7
AN XY:
692762
show subpopulations
Gnomad4 AFR exome
AF:
0.000502
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000462
Gnomad4 OTH exome
AF:
0.0000517
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.000434
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000982
ExAC
AF:
0.0000275
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Maple syrup urine disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 19, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the BCKDHB protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BCKDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 968447). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Maple syrup urine disease type 1B Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 21, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
.;T;T
Eigen
Benign
0.0027
Eigen_PC
Benign
0.061
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.55
T;.;T
M_CAP
Pathogenic
0.81
D
MetaRNN
Uncertain
0.59
D;D;D
MetaSVM
Uncertain
0.035
D
MutationAssessor
Benign
2.0
M;M;M
MutationTaster
Benign
0.99
N;N;N;N
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-0.46
N;N;N
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.94
.;P;P
Vest4
0.62
MutPred
0.31
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP
0.98
MPC
0.20
ClinPred
0.32
T
GERP RS
4.5
Varity_R
0.42
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769876670; hg19: chr6-80816415; API