rs2229413

Variant names:

• chr21-43071985-G-A
• rs2229413
• NM_000071.3:c.209C>T
• CBS p.Pro70Leu

Your query was ambiguous. Multiple possible variants found:

• chr21-43071985-G-A
• chr21-43071985-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000071.3(CBS):​c.209C>T​(p.Pro70Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P70R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.529
• Publications: 2 publications found

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: ClinGen, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02443254).
• BP6: Variant 21-43071985-G-A is Benign according to our data. Variant chr21-43071985-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212841.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.209C>T	p.Pro70Leu	missense splice_region	Exon 3 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000440 AC: 11 AN: 249920 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000790 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.19
DANN	Benign	0.39
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.53
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.32
Sift	Benign	0.66	T
Sift4G	Benign	0.70	T
Varity_R		0.21
gMVP		0.21
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.22
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2229413;

hg19: chr21-44492095;

COSMIC: COSV61444000;

COSMIC: COSV61444000;