Variant chr9-92502585-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001393.4(ECM2):c.1532T>C(p.Ile511Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ECM2
NM_001393.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.79

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECM2	NM_001393.4 link	c.1532T>C	p.Ile511Thr	missense_variant	8/10	ENST00000344604.10	NP_001384.1	O94769-1
CENPP	NM_001012267.3 link	c.565-108729A>G		intron_variant		ENST00000375587.8	NP_001012267.1	Q6IPU0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ECM2	ENST00000344604.10 link	c.1532T>C	p.Ile511Thr	missense_variant	8/10	1	NM_001393.4	ENSP00000344758.5	O94769-1
ECM2	ENST00000444490.6 link	c.1466T>C	p.Ile489Thr	missense_variant	8/10	1		ENSP00000393971.2	O94769-2
CENPP	ENST00000375587.8 link	c.565-108729A>G		intron_variant		1	NM_001012267.3	ENSP00000364737.3	Q6IPU0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458966

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.1532T>C (p.I511T) alteration is located in exon 8 (coding exon 7) of the ECM2 gene. This alteration results from a T to C substitution at nucleotide position 1532, causing the isoleucine (I) at amino acid position 511 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.71

.;N

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;D

Vest4

0.89

MutPred

0.71

.;Loss of stability (P = 0.0228);

MVP

0.85

MPC

0.31

ClinPred

0.99

GERP RS

5.8

Varity_R

0.60

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over