rs786200967

Positions:

• chr21-43063061-G-GGGTTCCACCTCGTAGGTTGTCTGCTCCGTCTGGTTCAGCTCCTCCGGCTCTGCGAGGATGGACCCTTC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The ENST00000398165.8(CBS):​c.845_846insGAAGGGTCCATCCTCGCAGAGCCGGAGGAGCTGAACCAGACGGAGCAGACAACCTACGAGGTGGAACC​(p.Glu283LysfsTer11) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P282P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 stop_gained, frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 21-43063061-G-GGGTTCCACCTCGTAGGTTGTCTGCTCCGTCTGGTTCAGCTCCTCCGGCTCTGCGAGGATGGACCCTTC is Benign according to our data. Variant chr21-43063061-G-GGGTTCCACCTCGTAGGTTGTCTGCTCCGTCTGGTTCAGCTCCTCCGGCTCTGCGAGGATGGACCCTTC is described in ClinVar as [Benign]. Clinvar id is 166800.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.845_846insGAAGGGTCCATCCTCGCAGAGCCGGAGGAGCTGAACCAGACGGAGCAGACAACCTACGAGGTGGAACC	p.Glu283LysfsTer11	stop_gained, frameshift_variant	10/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.845_846insGAAGGGTCCATCCTCGCAGAGCCGGAGGAGCTGAACCAGACGGAGCAGACAACCTACGAGGTGGAACC	p.Glu283LysfsTer11	stop_gained, frameshift_variant	10/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 03, 2014

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786200967; hg19: chr21-44483171;