9-92500728-G-A

Position:

• chr9-92500728-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001393.4(ECM2):​c.1930C>T​(p.Arg644Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,602,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: ECM2 NM_001393.4 missense, splice_region
• Scores: Splicing: ADA: 0.03779
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.431

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37346596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECM2	NM_001393.4	c.1930C>T	p.Arg644Trp	missense_variant, splice_region_variant	9/10	ENST00000344604.10
CENPP	NM_001012267.3	c.565-110586G>A		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECM2	ENST00000344604.10	c.1930C>T	p.Arg644Trp	missense_variant, splice_region_variant	9/10	1	NM_001393.4	P1
ECM2	ENST00000444490.6	c.1864C>T	p.Arg622Cys	missense_variant, splice_region_variant	9/10	1
CENPP	ENST00000375587.8	c.565-110586G>A		intron_variant		1	NM_001012267.3	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000130 AC: 32 AN: 246642 Hom.: 0 AF XY: 0.000165 AC XY: 22 AN XY: 133524

Gnomad AFR exome AF: 0.000815

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000383

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000669 AC: 97 AN: 1450206 Hom.: 0 Cov.: 31 AF XY: 0.0000681 AC XY: 49 AN XY: 719470

Gnomad4 AFR exome AF: 0.000789

Gnomad4 AMR exome AF: 0.0000917

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000820

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000435

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74312

Gnomad4 AFR AF: 0.000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000824 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.1930C>T (p.R644W) alteration is located in exon 9 (coding exon 8) of the ECM2 gene. This alteration results from a C to T substitution at nucleotide position 1930, causing the arginine (R) at amino acid position 644 to be replaced by a tryptophan (W). 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	0.28
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.75
ClinPred		0.33	T
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.20
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

Other links and lift over

dbSNP: rs151070730; hg19: chr9-95263010; COSMIC: COSV105909316;