Variant 9-92510019-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001393.4(ECM2):c.1186A>T(p.Met396Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,599,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 1 hom. )

Consequence

ECM2
NM_001393.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.529

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008528203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECM2	NM_001393.4 linkuse as main transcript	c.1186A>T	p.Met396Leu	missense_variant	6/10	ENST00000344604.10	NP_001384.1
CENPP	NM_001012267.3 linkuse as main transcript	c.565-101295T>A		intron_variant		ENST00000375587.8	NP_001012267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECM2	ENST00000344604.10 linkuse as main transcript	c.1186A>T	p.Met396Leu	missense_variant	6/10	1	NM_001393.4	ENSP00000344758	P1	O94769-1
ECM2	ENST00000444490.6 linkuse as main transcript	c.1120A>T	p.Met374Leu	missense_variant	6/10	1		ENSP00000393971		O94769-2
CENPP	ENST00000375587.8 linkuse as main transcript	c.565-101295T>A		intron_variant		1	NM_001012267.3	ENSP00000364737	P1	Q6IPU0-1

Frequencies

GnomAD3 genomes

AF:

0.000709

AC:

108

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000547

AC:

130

AN:

237810

Hom.:

AF XY:

0.000558

AC XY:

AN XY:

128952

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.000643

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000945

AC:

1368

AN:

1447550

Hom.:

Cov.:

AF XY:

0.000893

AC XY:

643

AN XY:

719890

show subpopulations

Gnomad4 AFR exome

AF:

0.000216

Gnomad4 AMR exome

AF:

0.000759

Gnomad4 ASJ exome

AF:

0.0000779

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000566

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000751

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152358

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000839

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000930

EpiControl

AF:

0.00107

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

Nov 30, 2022

The c.1186A>T (p.M396L) alteration is located in exon 6 (coding exon 5) of the ECM2 gene. This alteration results from a A to T substitution at nucleotide position 1186, causing the methionine (M) at amino acid position 396 to be replaced by a leucine (L). 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

Benign

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.8

DANN

Benign

0.77

DEOGEN2

Benign

0.013

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0085

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.98

.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.024

Sift

Benign

0.18

T;T

Sift4G

Uncertain

0.059

T;T

Polyphen

0.027

B;B

Vest4

0.17

MutPred

0.39

.;Loss of sheet (P = 0.0315);

MVP

0.49

MPC

0.057

ClinPred

0.0031

GERP RS

-4.3

Varity_R

0.12

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over