NM_000071.3:c.304A>C

Variant names:

• chr21-43068521-T-G
• rs34040148
• NM_000071.3:c.304A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BP6_Very_Strong

The NM_000071.3(CBS):​c.304A>C​(p.Lys102Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K102N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 6)
  • Exomes 𝑓: 0.0016 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.08
• Publications: 13 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: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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=0.012555659).
• BP6: Variant 21-43068521-T-G is Benign according to our data. Variant chr21-43068521-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.304A>C	p.Lys102Gln	missense	Exon 4 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.304A>C	p.Lys102Gln	missense	Exon 4 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.304A>C	p.Lys102Gln	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.304A>C	p.Lys102Gln	missense	Exon 4 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.304A>C	p.Lys102Gln	missense	Exon 4 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.304A>C	p.Lys102Gln	missense	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 514 AN: 39218 Hom.: 21 Cov.: 6

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000217

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00294 AC: 740 AN: 251336 AF XY: 0.00200

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00114

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00160 AC: 522 AN: 326162 Hom.: 12 Cov.: 0 AF XY: 0.00125 AC XY: 219 AN XY: 175858

African (AFR) AF: 0.0450 AC: 385 AN: 8558

American (AMR) AF: 0.00230 AC: 51 AN: 22142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10876

East Asian (EAS) AF: 0.00 AC: 0 AN: 25944

South Asian (SAS) AF: 0.0000472 AC: 2 AN: 42350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19530

Middle Eastern (MID) AF: 0.00147 AC: 2 AN: 1358

European-Non Finnish (NFE) AF: 0.000158 AC: 28 AN: 177404

Other (OTH) AF: 0.00300 AC: 54 AN: 18000

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0131 AC: 514 AN: 39308 Hom.: 21 Cov.: 6 AF XY: 0.0123 AC XY: 221 AN XY: 18028

African (AFR) AF: 0.0585 AC: 483 AN: 8250

American (AMR) AF: 0.00359 AC: 19 AN: 5292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1148

East Asian (EAS) AF: 0.00 AC: 0 AN: 1794

South Asian (SAS) AF: 0.00 AC: 0 AN: 966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.000217 AC: 4 AN: 18458

Other (OTH) AF: 0.0154 AC: 8 AN: 518

Alfa AF: 0.00423 Hom.: 24

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00362 AC: 440

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	3	Classic homocystinuria (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.58
Sift	Benign	0.10	T
Sift4G	Benign	0.091	T
Polyphen		0.56	P
Vest4		0.49
MVP		0.85
MPC		0.39
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.64
gMVP		0.80
Mutation Taster		=96/4	polymorphism

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: rs34040148; hg19: chr21-44488631;