rs786204608

Variant names:

• chr21-43068592-G-C
• rs786204608
• NM_000071.3:c.233C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP2 PP3_Strong

The NM_000071.3(CBS):​c.233C>G​(p.Pro78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P78P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 8.50
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• 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

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.233C>G	p.Pro78Arg	missense	Exon 4 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.233C>G	p.Pro78Arg	missense	Exon 4 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.233C>G	p.Pro78Arg	missense	Exon 4 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.233C>G	p.Pro78Arg	missense	Exon 4 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.233C>G	p.Pro78Arg	missense	Exon 4 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.233C>G	p.Pro78Arg	missense	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251194 AF XY: 0.00000736

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 365770 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 200272

African (AFR) AF: 0.00 AC: 0 AN: 8810

American (AMR) AF: 0.00 AC: 0 AN: 19620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11910

East Asian (EAS) AF: 0.00 AC: 0 AN: 26512

South Asian (SAS) AF: 0.00 AC: 0 AN: 45368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 210342

Other (OTH) AF: 0.00 AC: 0 AN: 20078

GnomAD4 genome Cov.: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.025	D
Sift4G	Benign	0.090	T
Polyphen		0.98	D
Vest4		0.90
MutPred		0.75		Gain of MoRF binding (P = 0.0014)
MVP		0.93
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.81
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs786204608; hg19: chr21-44488702;