chr21-43066310-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong

The NM_000071.3(CBS):​c.384G>C​(p.Glu128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E128E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 12)
Exomes 𝑓: 0.0000067 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

6
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.389

Publications

3 publications found
Variant links:
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]
CBS Gene-Disease associations (from GenCC):
  • classic homocystinuria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000071.3
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBSNM_000071.3 linkc.384G>C p.Glu128Asp missense_variant Exon 5 of 17 ENST00000398165.8 NP_000062.1 P35520-1Q9NTF0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBSENST00000398165.8 linkc.384G>C p.Glu128Asp missense_variant Exon 5 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
Cov.:
12
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251054
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000666
AC:
6
AN:
900284
Hom.:
0
Cov.:
13
AF XY:
0.00000863
AC XY:
4
AN XY:
463522
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
15316
American (AMR)
AF:
0.00
AC:
0
AN:
41580
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
20114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37524
South Asian (SAS)
AF:
0.00
AC:
0
AN:
69962
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36004
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3430
European-Non Finnish (NFE)
AF:
0.00000787
AC:
5
AN:
635636
Other (OTH)
AF:
0.0000246
AC:
1
AN:
40718
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D;D;D;.
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.73
D
LIST_S2
Pathogenic
0.98
.;.;.;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Uncertain
2.2
M;M;M;M;.
PhyloP100
0.39
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-2.7
D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.011
D;D;D;D;D
Sift4G
Uncertain
0.057
T;T;T;T;D
Polyphen
0.29
B;B;B;B;.
Vest4
0.94
MutPred
0.80
Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);
MVP
0.72
MPC
0.37
ClinPred
0.87
D
GERP RS
2.4
Varity_R
0.54
gMVP
0.85
Mutation Taster
=0/100
disease causing

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

Publications

Other links and lift over

dbSNP: rs374593242; hg19: chr21-44486420; API