rs773734233

Variant names:

• chr21-43065239-C-T
• rs773734233
• NM_000071.3:c.700G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.700G>A​(p.Asp234Asn) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249690: Published functional studies demonstrated that D234N expression in E. coli cells reduces CBS enzyme activity and D234N expression in Hek 293 cells leads to less soluble and fewer properly assembled subunits, suggesting D234N may lead to an unstable protein that is less able to assemble into a functional enzyme (Casique et al., 2014)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D234D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000086 (1 hom., cov: 15)
  • Exomes 𝑓: 0.000019 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.65
• Publications: 10 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249690: Published functional studies demonstrated that D234N expression in E. coli cells reduces CBS enzyme activity and D234N expression in Hek 293 cells leads to less soluble and fewer properly assembled subunits, suggesting D234N may lead to an unstable protein that is less able to assemble into a functional enzyme (Casique et al., 2014);; SCV000695308: The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60671), which does not exceed the estimated maximal expected allele frequency for a pathogenic CBS variant of 1/328 (0.0030414). The variant of interest has been reported in multiple affected individuals via publications including 2 homozygous individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. no; SCV001385812: Experimental studies have shown that this missense change affects CBS function (PMID: 22267502, 23981774).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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, 0.97
• PP5: Variant 21-43065239-C-T is Pathogenic according to our data. Variant chr21-43065239-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.700G>A	p.Asp234Asn	missense	Exon 8 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.700G>A	p.Asp234Asn	missense	Exon 8 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.700G>A	p.Asp234Asn	missense	Exon 8 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.700G>A	p.Asp234Asn	missense	Exon 8 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.700G>A	p.Asp234Asn	missense	Exon 8 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.700G>A	p.Asp234Asn	missense	Exon 8 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0000860 AC: 11 AN: 127908 Hom.: 1 Cov.: 15

Gnomad AFR AF: 0.0000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000389

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: 0.00176

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251422 AF XY: 0.0000147

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000193 AC: 25 AN: 1293816 Hom.: 4 Cov.: 28 AF XY: 0.0000186 AC XY: 12 AN XY: 644588

African (AFR) AF: 0.0000946 AC: 3 AN: 31702

American (AMR) AF: 0.0000465 AC: 2 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000162 AC: 13 AN: 80394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5206

European-Non Finnish (NFE) AF: 0.00000517 AC: 5 AN: 967296

Other (OTH) AF: 0.0000368 AC: 2 AN: 54398

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000860 AC: 11 AN: 127908 Hom.: 1 Cov.: 15 AF XY: 0.000113 AC XY: 7 AN XY: 62044

African (AFR) AF: 0.0000846 AC: 3 AN: 35474

American (AMR) AF: 0.000389 AC: 5 AN: 12850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2948

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 3922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56168

Other (OTH) AF: 0.00176 AC: 3 AN: 1708

Alfa AF: 0.0000420 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Classic homocystinuria (2)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L
PhyloP100		6.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.79		Loss of helix (P = 0.0558)
MVP		0.94
MPC		1.1
ClinPred		0.88	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs773734233; hg19: chr21-44485349; COSMIC: COSV61442631; COSMIC: COSV61442631;