rs769232573

Variant names:

• chr9-92505558-G-A
• rs769232573
• NM_001393.4:c.1439C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-92505558-G-A
• chr9-92505558-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001393.4(ECM2):​c.1439C>T​(p.Pro480Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,754 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: 0.0000028 (0 hom.)
• Consequence: ECM2 NM_001393.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.38
• Publications: 1 publications found

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]

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]

ACMG classification

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, 0.938

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM2	NM_001393.4	MANE Select	c.1439C>T	p.Pro480Leu	missense	Exon 7 of 10	NP_001384.1	O94769-1
	CENPP	NM_001012267.3	MANE Select	c.565-105756G>A		intron	N/A	NP_001012267.1	Q6IPU0-1
	ECM2	NM_001197295.2		c.1373C>T	p.Pro458Leu	missense	Exon 7 of 10	NP_001184224.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM2	ENST00000344604.10	TSL:1 MANE Select	c.1439C>T	p.Pro480Leu	missense	Exon 7 of 10	ENSP00000344758.5	O94769-1
	ECM2	ENST00000444490.6	TSL:1	c.1373C>T	p.Pro458Leu	missense	Exon 7 of 10	ENSP00000393971.2	O94769-2
	CENPP	ENST00000375587.8	TSL:1 MANE Select	c.565-105756G>A		intron	N/A	ENSP00000364737.3	Q6IPU0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000833 AC: 2 AN: 240194 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450754 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721164

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 41452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109286

Other (OTH) AF: 0.00 AC: 0 AN: 60014

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.81		Gain of MoRF binding (P = 0.0607)
MVP		0.90
MPC		0.39
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.72
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769232573; hg19: chr9-95267840;