chr8-98035666-T-C

Position:

• chr8-98035666-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000254898.7(MATN2):​c.2825T>C​(p.Met942Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,582,392 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: MATN2 ENST00000254898.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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:10333): (ribosomal protein L30) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L30E family of ribosomal proteins. It is located in the cytoplasm. This gene is co-transcribed with the U72 small nucleolar RNA gene, which is located in its fourth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011296362).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN2	NM_002380.5	c.2825T>C	p.Met942Thr	missense_variant	19/19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.2768T>C	p.Met923Thr	missense_variant	19/19		NP_085072.2
MATN2	NM_001317748.2	c.2702T>C	p.Met901Thr	missense_variant	18/18		NP_001304677.1
MATN2	XM_005250920.3	c.2411T>C	p.Met804Thr	missense_variant	18/18		XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000254898.7	c.2825T>C	p.Met942Thr	missense_variant	19/19	1	NM_002380.5	ENSP00000254898	P4

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00151 AC: 362 AN: 240104 Hom.: 3 AF XY: 0.00141 AC XY: 184 AN XY: 130310

Gnomad AFR exome AF: 0.000811

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00269 AC: 3846 AN: 1430114 Hom.: 7 Cov.: 26 AF XY: 0.00266 AC XY: 1896 AN XY: 712014

Gnomad4 AFR exome AF: 0.000519

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.000362

Gnomad4 NFE exome AF: 0.00330

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.00160 AC XY: 119 AN XY: 74438

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00245 Hom.: 0

Bravo AF: 0.00180

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000823 AC: 3

ESP6500EA AF: 0.00307 AC: 25

ExAC AF: 0.00127 AC: 153

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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

Apr 08, 2022

The c.2825T>C (p.M942T) alteration is located in exon 19 (coding exon 18) of the MATN2 gene. This alteration results from a T to C substitution at nucleotide position 2825, causing the methionine (M) at amino acid position 942 to be replaced by a threonine (T). 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	0.93
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	.;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;.;N;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;.;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.96	D;D;.;.;D
Vest4		0.60
MVP		0.79
MPC		0.22
ClinPred		0.022	T
GERP RS		5.9
Varity_R		0.88
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs151208737; hg19: chr8-99047894; COSMIC: COSV54719971; COSMIC: COSV54719971;