8-97961439-C-G

Variant summary

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

The NM_002380.5(MATN2):c.867C>G(p.Asn289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MATN2 NM_002380.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414

Genes affected

MATN2 (HGNC:6908): (matrilin 2) This gene encodes a member of the von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains five von Willebrand factor A domains. The specific function of this gene has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 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=0.36211595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN2	NM_002380.5	c.867C>G	p.Asn289Lys	missense_variant	5/19	ENST00000254898.7
MATN2	NM_030583.4	c.867C>G	p.Asn289Lys	missense_variant	5/19
MATN2	NM_001317748.2	c.867C>G	p.Asn289Lys	missense_variant	5/18
MATN2	XM_005250920.3	c.867C>G	p.Asn289Lys	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN2	ENST00000254898.7	c.867C>G	p.Asn289Lys	missense_variant	5/19	1	NM_002380.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248404 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461124 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726850

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

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

Dec 02, 2022

The c.867C>G (p.N289K) alteration is located in exon 5 (coding exon 4) of the MATN2 gene. This alteration results from a C to G substitution at nucleotide position 867, causing the asparagine (N) at amino acid position 289 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.68	T;T;T;T;.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.61	N;N;N;.;N;.
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Benign	0.071	T;T;T;T;T;T
Polyphen		0.057	B;B;.;.;B;.
Vest4		0.24
MutPred		0.73		Gain of ubiquitination at N289 (P = 0.0211);Gain of ubiquitination at N289 (P = 0.0211);Gain of ubiquitination at N289 (P = 0.0211);.;Gain of ubiquitination at N289 (P = 0.0211);.;
MVP		0.83
MPC		0.26
ClinPred		0.21	T
GERP RS		1.8
Varity_R		0.085
gMVP		0.48

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

Other links and lift over

dbSNP: rs1010621568; hg19: chr8-98973667;