11-102875061-T-C

Variant names:

• chr11-102875061-T-C
• rs2276109
• NM_002426.6:c.-124A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Moderate

The NM_002426.6(MMP12):c.-124A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.108 (AC=64,985) in the gnomAD database across 600,826 control chromosomes, including 4,255 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.127. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.092 (921 hom., cov: 33)
  • Exomes 𝑓: 0.11 (3334 hom.)
• Consequence: MMP12 NM_002426.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 176 publications found

Genes affected

MMP12 (HGNC:7158): (matrix metallopeptidase 12) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease degrades soluble and insoluble elastin. This gene may play a role in aneurysm formation and mutations in this gene are associated with lung function and chronic obstructive pulmonary disease (COPD). This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Moderate).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1275 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002426.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MMP12 NM_002426.6	MANE Select	c.-124A>G	upstream_gene	N/A	Prot: NP_002417.2 UniProt:

MMP12 NM_002426.6

MANE Select

HGVSc / HGVSpc.-124A>G

Exon rankN/A

upstream_gene

Prot: NP_002417.2UniProt: P39900

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MMP12 ENST00000571244.3	TSL:1MANE Select	c.-124A>G	upstream_gene	N/A	Prot: ENSP00000458585.1 UniProt:

MMP12 ENST00000571244.3

TSL:1MANE Select

HGVSc / HGVSpc.-124A>G

Exon rankN/A

upstream_gene

Prot: ENSP00000458585.1UniProt: P39900

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0922	AC:14026	Hom:920	AN:152134	Cov:33
GnomAD4 exome	AF: 0.114	AC:50958	Hom:3334	AN:448574	Cov:5
GnomAD4 genome	AF: 0.0921	AC:14027	Hom:921	AN:152252	Cov:33
TOPMed (Bravo)	AF: 0.0790	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0593	AC:2848	Hom:156	AN:47998	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0927	AC:217	Hom:10	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0272	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.170	AC:51	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.0490	AC:170	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0150	AC:108	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.108	AC:19	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0241	AC:2953	Hom:42	AN:122712	Cov:
Turkish Variome	AF: 0.120	AC:186	Hom:7	AN:1546	Cov:
UK10K	AF: 0.129	AC:974	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0265	AC:237	Hom:9	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0797	4964	62286	0.0813	7944	97688

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.4
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.71
GPN-Star LLR	N/A	-0.78
GPN-Star score	N/A	0.78
PhyloP100	Benign	-0.082
PromoterAI	N/A	-0.088	Neutral

Showing 8 of 8 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2276109;

hg19: chr11-102745791;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar