chr21-43066300-G-A

Variant names:

• chr21-43066300-G-A
• rs140002610
• NM_000071.3:c.394C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1 PP2 PP3_Moderate BS2

The NM_000071.3(CBS):​c.394C>T​(p.Arg132Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (8 hom., cov: 13)
  • Exomes 𝑓: 0.00063 (81 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1
• Conservation: PhyloP100: 0.676
• Publications: 1 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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, 10 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, 0.903
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.394C>T	p.Arg132Cys	missense	Exon 5 of 17	NP_000062.1
	CBS	NM_001178008.3		c.394C>T	p.Arg132Cys	missense	Exon 5 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.394C>T	p.Arg132Cys	missense	Exon 5 of 18	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.394C>T	p.Arg132Cys	missense	Exon 5 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.394C>T	p.Arg132Cys	missense	Exon 5 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.394C>T	p.Arg132Cys	missense	Exon 5 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 42 AN: 95256 Hom.: 8 Cov.: 13

Gnomad AFR AF: 0.0000619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000463

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000782

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 250812 AF XY: 0.000251

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000628 AC: 596 AN: 949052 Hom.: 81 Cov.: 14 AF XY: 0.000590 AC XY: 287 AN XY: 486258

African (AFR) AF: 0.000316 AC: 5 AN: 15834

American (AMR) AF: 0.0000239 AC: 1 AN: 41860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20474

East Asian (EAS) AF: 0.000502 AC: 19 AN: 37826

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 71064

European-Finnish (FIN) AF: 0.000109 AC: 4 AN: 36732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3656

European-Non Finnish (NFE) AF: 0.000820 AC: 557 AN: 679148

Other (OTH) AF: 0.000212 AC: 9 AN: 42458

GnomAD4 genome AF: 0.000441 AC: 42 AN: 95256 Hom.: 8 Cov.: 13 AF XY: 0.000304 AC XY: 14 AN XY: 46064

African (AFR) AF: 0.0000619 AC: 1 AN: 16166

American (AMR) AF: 0.00 AC: 0 AN: 11002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2506

East Asian (EAS) AF: 0.000463 AC: 2 AN: 4316

South Asian (SAS) AF: 0.00 AC: 0 AN: 3068

European-Finnish (FIN) AF: 0.000135 AC: 1 AN: 7434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.000782 AC: 38 AN: 48602

Other (OTH) AF: 0.00 AC: 0 AN: 1302

Alfa AF: 0.000439 Hom.: 0

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	-	Classic homocystinuria (6)
-	4	1	not provided (5)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	Intellectual disability (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.68
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.88
MPC		1.2
ClinPred		0.85	D
GERP RS		3.2
Varity_R		0.80
gMVP		0.76
Mutation Taster		=37/63	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: rs140002610; hg19: chr21-44486410;