ENST00000522025:c.-107G>T

Variant names:

• chr8-97941810-G-T
• ENST00000522025:c.-107G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000522025(MATN2):​c.-107G>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MATN2 ENST00000522025 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN2	NM_002380.5	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 19		NP_085072.2
MATN2	NM_001317748.2	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 18		NP_001304677.1
MATN2	XM_005250920.3	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 18		XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000522025	c.-107G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 18	5		ENSP00000429010.1
MATN2	ENST00000254898.7	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 19	1	NM_002380.5	ENSP00000254898.6
MATN2	ENST00000520016.5	c.746G>T	p.Cys249Phe	missense_variant	Exon 3 of 18	1		ENSP00000430487.1
MATN2	ENST00000521689.5	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 19	1		ENSP00000429977.1
MATN2	ENST00000524308.5	c.746G>T	p.Cys249Phe	missense_variant	Exon 4 of 18	1		ENSP00000430221.1
MATN2	ENST00000518154.5	c.215G>T	p.Cys72Phe	missense_variant	Exon 2 of 16	1		ENSP00000429622.1
MATN2	ENST00000522025	c.-107G>T		5_prime_UTR_variant	Exon 3 of 18	5		ENSP00000429010.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746G>T (p.C249F) alteration is located in exon 4 (coding exon 3) of the MATN2 gene. This alteration results from a G to T substitution at nucleotide position 746, causing the cysteine (C) at amino acid position 249 to be replaced by a phenylalanine (F). 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	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H;H;H;H
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.2	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.95	P;D;.;D
Vest4		0.90
MutPred		0.86		Gain of catalytic residue at C249 (P = 0.1149);Gain of catalytic residue at C249 (P = 0.1149);Gain of catalytic residue at C249 (P = 0.1149);Gain of catalytic residue at C249 (P = 0.1149);
MVP		1.0
MPC		0.94
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-98954038;