chr8-98032271-G-C

Position:

• chr8-98032271-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000254898.7(MATN2):​c.2535G>C​(p.Gln845His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.9e-7 (0 hom.)
• Consequence: MATN2 ENST00000254898.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.299

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15488154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN2	NM_002380.5	c.2535G>C	p.Gln845His	missense_variant	16/19	ENST00000254898.7	NP_002371.3
MATN2	NM_030583.4	c.2535G>C	p.Gln845His	missense_variant	16/19		NP_085072.2
MATN2	NM_001317748.2	c.2412G>C	p.Gln804His	missense_variant	15/18		NP_001304677.1
MATN2	XM_005250920.3	c.2121G>C	p.Gln707His	missense_variant	15/18		XP_005250977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN2	ENST00000254898.7	c.2535G>C	p.Gln845His	missense_variant	16/19	1	NM_002380.5	ENSP00000254898	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459746 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 13, 2022

The c.2535G>C (p.Q845H) alteration is located in exon 16 (coding exon 15) of the MATN2 gene. This alteration results from a G to C substitution at nucleotide position 2535, causing the glutamine (Q) at amino acid position 845 to be replaced by a histidine (H). 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	0.15
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D;D;D;D;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;L;.;.;L
MutationTaster	Benign	0.57	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.81	N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.043	D;T;T;D;T
Sift4G	Benign	0.10	T;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.18
MutPred		0.13		Gain of glycosylation at S841 (P = 0.1274);Gain of glycosylation at S841 (P = 0.1274);.;.;Gain of glycosylation at S841 (P = 0.1274);
MVP		0.87
MPC		0.45
ClinPred		0.76	D
GERP RS		0.92
Varity_R		0.055
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1459378998; hg19: chr8-99044499;