Genetic Variant NM_001320298.2:c.-251G>C (chr21-43076866-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001320298.2(CBS):c.-251G>C variant causes a 5 prime UTR 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 Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 51950 hom., cov: 20)

Exomes 𝑓: 0.85 ( 20 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_001320298.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.00

Publications

17 publications found

Variant links:

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

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 21-43076866-C-G is Benign according to our data. Variant chr21-43076866-C-G is described in ClinVar as Benign. ClinVar VariationId is 1168575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
CBS	NM_001320298.2 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 18	NP_001307227.1
CBS	XM_047441024.1 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 19	XP_047296980.1
CBS	XM_047441025.1 link	c.-686G>C	5_prime_UTR_variant	Exon 1 of 20	XP_047296981.1
CBS	XM_047441030.1 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 19	XP_047296986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000441030.5 link	c.-211G>C		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000388235.1

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

113408

AN:

129004

Hom.:

51920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.847

Gnomad AMI

AF:

0.869

Gnomad AMR

AF:

0.717

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.881

Gnomad SAS

AF:

0.873

Gnomad FIN

AF:

0.906

Gnomad MID

AF:

0.893

Gnomad NFE

AF:

0.934

Gnomad OTH

AF:

0.883

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.852

AC:

AN:

Hom.:

Cov.:

AF XY:

0.857

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.667

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.905

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.583

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.879

AC:

113479

AN:

129092

Hom.:

51950

Cov.:

AF XY:

0.874

AC XY:

54201

AN XY:

62046

show subpopulations

African (AFR)

AF:

0.847

AC:

33146

AN:

39132

American (AMR)

AF:

0.716

AC:

9197

AN:

12840

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

2686

AN:

3002

East Asian (EAS)

AF:

0.881

AC:

3691

AN:

4188

South Asian (SAS)

AF:

0.873

AC:

3305

AN:

3786

European-Finnish (FIN)

AF:

0.906

AC:

6312

AN:

6966

Middle Eastern (MID)

AF:

0.883

AC:

233

AN:

264

European-Non Finnish (NFE)

AF:

0.934

AC:

52793

AN:

56510

Other (OTH)

AF:

0.884

AC:

1577

AN:

1784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

452

904

1355

1807

2259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.656

Hom.:

1546

Asia WGS

AF:

0.666

AC:

2313

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.90

(source)

DANN

Benign

0.45

PhyloP100

-3.0

PromoterAI

-0.12

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over