Genetic Variant MAD2L2:c.-12-1404G>A (chr1-11682017-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000376672.5(MAD2L2):c.-12-1404G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,080 control chromosomes in the GnomAD database, including 51,630 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.82 ( 51630 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

MAD2L2
ENST00000376672.5 intron

Scores

Splicing: ADA: 0.00002930

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.725

Publications

14 publications found

Variant links:

Genes affected

MAD2L2 (HGNC:6764): (mitotic arrest deficient 2 like 2) The protein encoded by this gene is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. The encoded protein, which is similar to MAD2L1, is capable of interacting with ADAM9, ADAM15, REV1, and REV3 proteins. [provided by RefSeq, Jul 2008]

MAD2L2 Gene-Disease associations (from GenCC):

Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia complementation group V
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MAD2L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376672.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD2L2	NM_001127325.2		c.-12-1404G>A		intron	N/A	NP_001120797.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MAD2L2	ENST00000376672.5	TSL:3	c.-12-1404G>A	intron	N/A	ENSP00000365860.1
MAD2L2	ENST00000235310.7	TSL:2	c.-691-1G>A	splice_acceptor intron	N/A	ENSP00000235310.2
MAD2L2	ENST00000376667.7	TSL:2	c.-12-1404G>A	intron	N/A	ENSP00000365855.3

Frequencies

GnomAD3 genomes

AF:

0.821

AC:

124828

AN:

151962

Hom.:

51589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.878

Gnomad AMI

AF:

0.638

Gnomad AMR

AF:

0.841

Gnomad ASJ

AF:

0.748

Gnomad EAS

AF:

0.936

Gnomad SAS

AF:

0.807

Gnomad FIN

AF:

0.900

Gnomad MID

AF:

0.722

Gnomad NFE

AF:

0.770

Gnomad OTH

AF:

0.811

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.821

AC:

124928

AN:

152080

Hom.:

51630

Cov.:

AF XY:

0.827

AC XY:

61426

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.878

AC:

36426

AN:

41474

American (AMR)

AF:

0.841

AC:

12838

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.748

AC:

2596

AN:

3470

East Asian (EAS)

AF:

0.935

AC:

4837

AN:

5172

South Asian (SAS)

AF:

0.806

AC:

3869

AN:

4802

European-Finnish (FIN)

AF:

0.900

AC:

9519

AN:

10578

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.770

AC:

52335

AN:

68004

Other (OTH)

AF:

0.813

AC:

1718

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1148

2295

3443

4590

5738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.783

Hom.:

119050

Bravo

AF:

0.820

Asia WGS

AF:

0.879

AC:

3057

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.8

(source)

DANN

Benign

0.68

PhyloP100

-0.72

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over