Genetic Variant NM_006341.4:c.254T>G (chr1-11676926-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_006341.4(MAD2L2):c.254T>G(p.Val85Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V85E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MAD2L2
NM_006341.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.87

Publications

5 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11676926-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372196.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006341.4. 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_006341.4	MANE Select	c.254T>G	p.Val85Gly	missense	Exon 5 of 9	NP_006332.3
	MAD2L2	NM_001127325.2		c.254T>G	p.Val85Gly	missense	Exon 5 of 9	NP_001120797.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAD2L2	ENST00000376692.9	TSL:1 MANE Select	c.254T>G	p.Val85Gly	missense	Exon 5 of 9	ENSP00000365882.4
MAD2L2	ENST00000856191.1		c.344T>G	p.Val115Gly	missense	Exon 4 of 8	ENSP00000526250.1
MAD2L2	ENST00000856194.1		c.344T>G	p.Val115Gly	missense	Exon 4 of 8	ENSP00000526253.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.099

MutationAssessor

Uncertain

2.8

PhyloP100

8.9

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.049

Polyphen

0.99

Vest4

0.57

MutPred

0.69

Loss of stability (P = 0.0689)

MVP

0.80

MPC

2.0

ClinPred

0.99

GERP RS

5.6

Varity_R

0.93

gMVP

0.98

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over