rs192232907

Variant names:

• chr21-43068610-T-A
• rs192232907
• NM_000071.3:c.215A>T
• CBS p.Lys72Ile

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000071.3(CBS):​c.215A>T​(p.Lys72Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K72K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 5)
  • Exomes 𝑓: 0.00027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 1.02
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007154703).
• BP6: Variant 21-43068610-T-A is Benign according to our data. Variant chr21-43068610-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212883.

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.215A>T	p.Lys72Ile	missense	Exon 4 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.215A>T	p.Lys72Ile	missense	Exon 4 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.215A>T	p.Lys72Ile	missense	Exon 4 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.215A>T	p.Lys72Ile	missense	Exon 4 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.215A>T	p.Lys72Ile	missense	Exon 4 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.215A>T	p.Lys72Ile	missense	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0000489 AC: 2 AN: 40890 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00106

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000626 AC: 157 AN: 250818 AF XY: 0.000553

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00740

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000327

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000270 AC: 100 AN: 371044 Hom.: 0 Cov.: 0 AF XY: 0.000211 AC XY: 43 AN XY: 204022

African (AFR) AF: 0.00 AC: 0 AN: 8682

American (AMR) AF: 0.00 AC: 0 AN: 22734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12730

East Asian (EAS) AF: 0.00290 AC: 75 AN: 25884

South Asian (SAS) AF: 0.000281 AC: 13 AN: 46232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1592

European-Non Finnish (NFE) AF: 0.0000284 AC: 6 AN: 211432

Other (OTH) AF: 0.000299 AC: 6 AN: 20046

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000489 AC: 2 AN: 40898 Hom.: 0 Cov.: 5 AF XY: 0.0000520 AC XY: 1 AN XY: 19226

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7650

American (AMR) AF: 0.00 AC: 0 AN: 6104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1294

East Asian (EAS) AF: 0.00107 AC: 2 AN: 1872

South Asian (SAS) AF: 0.00 AC: 0 AN: 1328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 19210

Other (OTH) AF: 0.00 AC: 0 AN: 588

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000893 Hom.: 0

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Classic homocystinuria (2)
-	2	-	not provided (2)
-	-	1	CBS-related disorder (1)
-	1	-	Connective tissue disorder (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0072	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.36
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Varity_R		0.68
gMVP		0.62
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

dbSNP: rs192232907;

hg19: chr21-44488720;

COSMIC: COSV100657892;

COSMIC: COSV100657892;