rs121964969

Variant names:

• chr21-43063931-C-T
• rs121964969
• NM_000071.3:c.797G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-43063931-C-T
• chr21-43063931-C-G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000071.3(CBS):​c.797G>A​(p.Arg266Lys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.85
• Publications: 36 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 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43063932-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2680419.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.912
• PP5: Variant 21-43063931-C-T is Pathogenic according to our data. Variant chr21-43063931-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 125.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.797G>A	p.Arg266Lys	missense	Exon 9 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.797G>A	p.Arg266Lys	missense	Exon 9 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.797G>A	p.Arg266Lys	missense	Exon 9 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.797G>A	p.Arg266Lys	missense	Exon 9 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.797G>A	p.Arg266Lys	missense	Exon 9 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.797G>A	p.Arg266Lys	missense	Exon 9 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249680 AF XY: 0.00000740

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 3 AN: 205802 Hom.: 0 Cov.: 0 AF XY: 0.0000183 AC XY: 2 AN XY: 109370

African (AFR) AF: 0.00 AC: 0 AN: 7084

American (AMR) AF: 0.00 AC: 0 AN: 12162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5258

East Asian (EAS) AF: 0.00 AC: 0 AN: 21842

South Asian (SAS) AF: 0.00 AC: 0 AN: 28834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 804

European-Non Finnish (NFE) AF: 0.0000281 AC: 3 AN: 106612

Other (OTH) AF: 0.00 AC: 0 AN: 11364

GnomAD4 genome Cov.: 4

Alfa AF: 0.0000280 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Classic homocystinuria (2)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	Homocystinuria, pyridoxine-responsive (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.99	L
PhyloP100		6.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.84
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.77	P
Vest4		0.92
MVP		0.90
MPC		0.95
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.85
gMVP		0.94
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: rs121964969; hg19: chr21-44484041;