8-98027434-T-C

Position:

• chr8-98027434-T-C

Variant summary

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

The ENST00000254898.7(MATN2):​c.1961T>C​(p.Ile654Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,453,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MATN2 ENST00000254898.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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 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=0.2957354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN2	NM_002380.5	c.1961T>C	p.Ile654Thr	missense_variant	14/19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.1961T>C	p.Ile654Thr	missense_variant	14/19		NP_085072.2
MATN2	NM_001317748.2	c.1838T>C	p.Ile613Thr	missense_variant	13/18		NP_001304677.1
MATN2	XM_005250920.3	c.1943-3028T>C		intron_variant			XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000254898.7	c.1961T>C	p.Ile654Thr	missense_variant	14/19	1	NM_002380.5	ENSP00000254898	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248248 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1453888 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 16 AN XY: 721454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000301 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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 28, 2023

The c.1961T>C (p.I654T) alteration is located in exon 14 (coding exon 13) of the MATN2 gene. This alteration results from a T to C substitution at nucleotide position 1961, causing the isoleucine (I) at amino acid position 654 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	Benign	0.23
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.061	.;T;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.000040
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;T;T;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.32	N;N;.;.;N
MutationTaster	Benign	0.91	D;D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.12	B;B;.;.;B
Vest4		0.33
MutPred		0.50		Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);.;.;Loss of stability (P = 0.0209);
MVP		0.85
MPC		0.29
ClinPred		0.19	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.63

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: rs753482533; hg19: chr8-99039662;