8-97931405-G-T

Variant names:

• chr8-97931405-G-T
• rs758001116
• NM_002380.5:c.595G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002380.5(MATN2):​c.595G>T​(p.Val199Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MATN2 NM_002380.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN2	NM_002380.5	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 19		NP_085072.2
MATN2	NM_001317748.2	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 18		NP_001304677.1
MATN2	XM_005250920.3	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 18		XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000254898.7	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 19	1	NM_002380.5	ENSP00000254898.6
MATN2	ENST00000520016.5	c.595G>T	p.Val199Leu	missense_variant	Exon 2 of 18	1		ENSP00000430487.1
MATN2	ENST00000521689.5	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 19	1		ENSP00000429977.1
MATN2	ENST00000524308.5	c.595G>T	p.Val199Leu	missense_variant	Exon 3 of 18	1		ENSP00000430221.1
MATN2	ENST00000518154.5	c.64G>T	p.Val22Leu	missense_variant	Exon 1 of 16	1		ENSP00000429622.1
MATN2	ENST00000522025.6	c.-115+865G>T		intron_variant	Intron 2 of 17	5		ENSP00000429010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248382 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134864

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: 0.0000534

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461434 Hom.: 0 Cov.: 34 AF XY: 0.0000248 AC XY: 18 AN XY: 727014

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595G>T (p.V199L) alteration is located in exon 3 (coding exon 2) of the MATN2 gene. This alteration results from a G to T substitution at nucleotide position 595, causing the valine (V) at amino acid position 199 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;.
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.6	L;L;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;D;T;D
Sift4G	Uncertain	0.032	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.64
MutPred		0.63		Gain of catalytic residue at V199 (P = 0.0905);Gain of catalytic residue at V199 (P = 0.0905);Gain of catalytic residue at V199 (P = 0.0905);Gain of catalytic residue at V199 (P = 0.0905);
MVP		0.94
MPC		0.75
ClinPred		0.70	D
GERP RS		6.0
Varity_R		0.42
gMVP		0.92

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: rs758001116; hg19: chr8-98943633;