Genetic Variant ECM2:p.Pro480Gln (chr9-92505558-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001393.4(ECM2):c.1439C>A(p.Pro480Gln) 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. P480L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ECM2
NM_001393.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.38

Publications

1 publications found

Variant links:

Genes affected

ECM2 (HGNC:3154): (extracellular matrix protein 2) ECM2 encodes extracellular matrix protein 2, so named because it shares extensive similarity with known extracelluar matrix proteins. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

ECM2 links:

CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

CENPP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECM2	NM_001393.4	MANE Select	c.1439C>A	p.Pro480Gln	missense	Exon 7 of 10	NP_001384.1	O94769-1
CENPP	NM_001012267.3	MANE Select	c.565-105756G>T		intron	N/A	NP_001012267.1	Q6IPU0-1
ECM2	NM_001197295.2		c.1373C>A	p.Pro458Gln	missense	Exon 7 of 10	NP_001184224.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECM2	ENST00000344604.10	TSL:1 MANE Select	c.1439C>A	p.Pro480Gln	missense	Exon 7 of 10	ENSP00000344758.5	O94769-1
ECM2	ENST00000444490.6	TSL:1	c.1373C>A	p.Pro458Gln	missense	Exon 7 of 10	ENSP00000393971.2	O94769-2
CENPP	ENST00000375587.8	TSL:1 MANE Select	c.565-105756G>T		intron	N/A	ENSP00000364737.3	Q6IPU0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000416

AC:

AN:

240194

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.1

PhyloP100

9.4

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.90

MutPred

0.77

Loss of catalytic residue at P480 (P = 0.0215)

MVP

0.93

MPC

0.37

ClinPred

1.0

GERP RS

5.6

Varity_R

0.89

gMVP

0.71

Mutation Taster

=14/86

disease causing

(source)

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

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