8-97888141-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002380.5(MATN2):c.41G>C(p.Gly14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,609,544 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0060 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (8 hom.)
• Consequence: MATN2 NM_002380.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.75

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066571236).
• BP6: Variant 8-97888141-G-C is Benign according to our data. Variant chr8-97888141-G-C is described in ClinVar as [Benign]. Clinvar id is 778943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (921/152290) while in subpopulation AFR AF= 0.0213 (886/41564). AF 95% confidence interval is 0.0202. There are 15 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN2	NM_002380.5	c.41G>C	p.Gly14Ala	missense_variant	2/19	ENST00000254898.7
MATN2	NM_030583.4	c.41G>C	p.Gly14Ala	missense_variant	2/19
MATN2	NM_001317748.2	c.41G>C	p.Gly14Ala	missense_variant	2/18
MATN2	XM_005250920.3	c.41G>C	p.Gly14Ala	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN2	ENST00000254898.7	c.41G>C	p.Gly14Ala	missense_variant	2/19	1	NM_002380.5	P4

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152172 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00148 AC: 361 AN: 244390 Hom.: 4 AF XY: 0.00108 AC XY: 143 AN XY: 132828

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.000882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000683

GnomAD4 exome AF: 0.000609 AC: 887 AN: 1457254 Hom.: 8 Cov.: 30 AF XY: 0.000494 AC XY: 358 AN XY: 724862

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.000959

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152290 Hom.: 15 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74460

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000998 Hom.: 2

Bravo AF: 0.00670

ESP6500AA AF: 0.0200 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T;T;T;.
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.22	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.089	T;T;T;T
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.79	P;P;.;P
Vest4		0.26
MVP		0.88
MPC		0.21
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.063
gMVP		0.57

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: rs35804177; hg19: chr8-98900369; COSMIC: COSV99073856;