8-97941777-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002380.5(MATN2):c.713C>T(p.Thr238Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,586,000 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: MATN2 NM_002380.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001921
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.240

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024647057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN2	NM_002380.5	c.713C>T	p.Thr238Met	missense_variant, splice_region_variant	4/19	ENST00000254898.7
MATN2	NM_030583.4	c.713C>T	p.Thr238Met	missense_variant, splice_region_variant	4/19
MATN2	NM_001317748.2	c.713C>T	p.Thr238Met	missense_variant, splice_region_variant	4/18
MATN2	XM_005250920.3	c.713C>T	p.Thr238Met	missense_variant, splice_region_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN2	ENST00000254898.7	c.713C>T	p.Thr238Met	missense_variant, splice_region_variant	4/19	1	NM_002380.5	P4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000153 AC: 32 AN: 209346 Hom.: 0 AF XY: 0.000169 AC XY: 19 AN XY: 112316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000495

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 184 AN: 1433736 Hom.: 2 Cov.: 29 AF XY: 0.000132 AC XY: 94 AN XY: 710578

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.000619

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000947

Gnomad4 OTH exome AF: 0.000118

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74456

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000190 AC: 23

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

Jun 22, 2023

The c.713C>T (p.T238M) alteration is located in exon 4 (coding exon 3) of the MATN2 gene. This alteration results from a C to T substitution at nucleotide position 713, causing the threonine (T) at amino acid position 238 to be replaced by a methionine (M). 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	0.071
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	4.1
Dann	Benign	0.84
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.29	T;T;T;.
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.025	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.047	D;T;T;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.012	B;B;.;B
Vest4		0.080
MVP		0.60
MPC		0.20
ClinPred		0.036	T
GERP RS		-2.7
Varity_R		0.026
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.12
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: rs199768448; hg19: chr8-98954005; COSMIC: COSV99646459;