1-11676926-A-C

Position:

• chr1-11676926-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 372196.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAD2L2	NM_006341.4	c.254T>G	p.Val85Gly	missense_variant	5/9	ENST00000376692.9	NP_006332.3
MAD2L2	NM_001127325.2	c.254T>G	p.Val85Gly	missense_variant	5/9		NP_001120797.1
MAD2L2	XM_047430782.1	c.254T>G	p.Val85Gly	missense_variant	5/9		XP_047286738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAD2L2	ENST00000376692.9	c.254T>G	p.Val85Gly	missense_variant	5/9	1	NM_006341.4	ENSP00000365882.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T;T;T;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;T;.;T;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Uncertain	2.8	M;M;.;.;M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.049	D;D;D;D;D;.;.
Polyphen		0.99	D;D;.;.;D;.;.
Vest4		0.57
MutPred		0.69		Loss of stability (P = 0.0689);Loss of stability (P = 0.0689);Loss of stability (P = 0.0689);Loss of stability (P = 0.0689);Loss of stability (P = 0.0689);.;Loss of stability (P = 0.0689);
MVP		0.80
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs1057517674; hg19: chr1-11736983;