21-43065417-G-C

Variant names:

• chr21-43065417-G-C
• rs2298758
• NM_000071.3:c.636C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_000071.3(CBS):​c.636C>G​(p.Asn212Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N212N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.00019 (19 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.783
• Publications: 7 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: Likely_benign. The variant received -3 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.051193625).

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.636C>G	p.Asn212Lys	missense	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.636C>G	p.Asn212Lys	missense	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.636C>G	p.Asn212Lys	missense	Exon 7 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.636C>G	p.Asn212Lys	missense	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.636C>G	p.Asn212Lys	missense	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.636C>G	p.Asn212Lys	missense	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 250098 AF XY: 0.000185

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: 0.000187 AC: 84 AN: 448080 Hom.: 19 Cov.: 4 AF XY: 0.000321 AC XY: 77 AN XY: 239924

African (AFR) AF: 0.00 AC: 0 AN: 13762

American (AMR) AF: 0.00 AC: 0 AN: 30862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15034

East Asian (EAS) AF: 0.00 AC: 0 AN: 31418

South Asian (SAS) AF: 0.00148 AC: 83 AN: 56006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1930

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 245764

Other (OTH) AF: 0.0000406 AC: 1 AN: 24620

GnomAD4 genome Cov.: 5

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Classic homocystinuria (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.017
DANN	Benign	0.74
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-1.7	N
PhyloP100		-0.78
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.78	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.60
MutPred		0.38		Gain of ubiquitination at N212 (P = 0.0289)
MVP		0.21
MPC		0.40
ClinPred		0.0097	T
GERP RS		-6.6
Varity_R		0.18
gMVP		0.76
Mutation Taster		=29/71	disease causing

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: rs2298758; hg19: chr21-44485527;