21-43058926-CGG-TCT

Variant names:

• chr21-43058926-CGG-TCT
• NM_000071.3:c.1264_1266delCCGinsAGA
• CBS p.Pro422Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP2 PP3

The NM_000071.3(CBS):​c.1264_1266delCCGinsAGA​(p.Pro422Arg) variant causes a missense change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P422L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.46
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43058927-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	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.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1264_1266delCCGinsAGA	p.Pro422Arg	missense	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

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

hg19: chr21-44479036;