rs376333101

Variant names:

• chr9-92505589-G-A
• rs376333101
• NM_001393.4:c.1408C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-92505589-G-A
• chr9-92505589-G-T
• chr9-92505589-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001393.4(ECM2):​c.1408C>T​(p.Arg470Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000354 in 1,608,646 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ECM2 NM_001393.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

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.1408C>T	p.Arg470Cys	missense	Exon 7 of 10	NP_001384.1	O94769-1
	CENPP	NM_001012267.3	MANE Select	c.565-105725G>A		intron	N/A	NP_001012267.1	Q6IPU0-1
	ECM2	NM_001197295.2		c.1342C>T	p.Arg448Cys	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.1408C>T	p.Arg470Cys	missense	Exon 7 of 10	ENSP00000344758.5	O94769-1
	ECM2	ENST00000444490.6	TSL:1	c.1342C>T	p.Arg448Cys	missense	Exon 7 of 10	ENSP00000393971.2	O94769-2
	CENPP	ENST00000375587.8	TSL:1 MANE Select	c.565-105725G>A		intron	N/A	ENSP00000364737.3	Q6IPU0-1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000527 AC: 13 AN: 246576 AF XY: 0.0000451

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1456578 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 32 AN XY: 724236

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.0000230 AC: 1 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 39 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110652

Other (OTH) AF: 0.0000830 AC: 5 AN: 60216

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.00

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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.063	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.88
MPC		0.43
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.71
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs376333101; hg19: chr9-95267871;