8-98027442-G-A

Position:

• chr8-98027442-G-A

Variant summary

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

The NM_002380.5(MATN2):​c.1969G>A​(p.Val657Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MATN2 NM_002380.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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]

RPL30 (HGNC:):

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=0.31164253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN2	NM_002380.5	c.1969G>A	p.Val657Ile	missense_variant	14/19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.1969G>A	p.Val657Ile	missense_variant	14/19		NP_085072.2
MATN2	NM_001317748.2	c.1846G>A	p.Val616Ile	missense_variant	13/18		NP_001304677.1
MATN2	XM_005250920.3	c.1943-3020G>A		intron_variant			XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000254898.7	c.1969G>A	p.Val657Ile	missense_variant	14/19	1	NM_002380.5	ENSP00000254898.6
MATN2	ENST00000520016.5	c.1969G>A	p.Val657Ile	missense_variant	13/18	1		ENSP00000430487.1
MATN2	ENST00000521689.5	c.1969G>A	p.Val657Ile	missense_variant	14/19	1		ENSP00000429977.1
MATN2	ENST00000524308.5	c.1846G>A	p.Val616Ile	missense_variant	13/18	1		ENSP00000430221.1
MATN2	ENST00000518154.5	c.1315G>A	p.Val439Ile	missense_variant	11/16	1		ENSP00000429622.1
MATN2	ENST00000522025.6	c.1117G>A	p.Val373Ile	missense_variant	13/18	5		ENSP00000429010.1
MATN2	ENST00000521952.5	n.*25-3020G>A		intron_variant		5		ENSP00000429256.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248878 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135014

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458188 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 15, 2024

The c.1969G>A (p.V657I) alteration is located in exon 14 (coding exon 13) of the MATN2 gene. This alteration results from a G to A substitution at nucleotide position 1969, causing the valine (V) at amino acid position 657 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;.;T
Eigen	Benign	-0.0031
Eigen_PC	Benign	0.090
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.5	M;M;.;.;M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.021	D;D;T;T;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.10	B;B;.;.;B
Vest4		0.24
MutPred		0.61		Loss of stability (P = 0.2906);Loss of stability (P = 0.2906);.;.;Loss of stability (P = 0.2906);
MVP		0.90
MPC		0.33
ClinPred		0.81	D
GERP RS		3.3
Varity_R		0.096
gMVP		0.43

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: rs1316923885; hg19: chr8-99039670;