rs2499953

Variant names:

• chr11-4989675-A-G
• rs2499953
• NM_021801.5:c.127A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-4989675-A-G
• chr11-4989675-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021801.5(MMP26):​c.127A>G​(p.Lys43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,612,874 control chromosomes in the GnomAD database, including 5,990 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1731 hom., cov: 32)
  • Exomes 𝑓: 0.039 (4259 hom.)
• Consequence: MMP26 NM_021801.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 25 publications found

Genes affected

MMP26 (HGNC:14249): (matrix metallopeptidase 26) Proteins of the matrix metalloproteinase (MMP) 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 enzyme. This enzyme may degrade collagen type IV, fibronectin, fibrinogen, and beta-casein, and activate matrix metalloproteinase-9 by cleavage. The protein differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The encoded protein may promote cell invasion in multiple human cancers. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045666993).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP26	NM_021801.5	c.127A>G	p.Lys43Glu	missense_variant	Exon 4 of 8	ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-84A>G		5_prime_UTR_variant	Exon 4 of 8		NP_001371537.1
MMP26	XM_011520219.3	c.-84A>G		5_prime_UTR_variant	Exon 3 of 7		XP_011518521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP26	ENST00000380390.6	c.127A>G	p.Lys43Glu	missense_variant	Exon 4 of 8	5	NM_021801.5	ENSP00000369753.1
MMP26	ENST00000300762.2	c.-84A>G		5_prime_UTR_variant	Exon 4 of 8	1		ENSP00000300762.2
MMP26	ENST00000690848.1	c.127A>G	p.Lys43Glu	missense_variant	Exon 3 of 7			ENSP00000510347.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16360 AN: 151930 Hom.: 1726 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.0568

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.0862 AC: 21497 AN: 249378 AF XY: 0.0747

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0393 AC: 57426 AN: 1460826 Hom.: 4259 Cov.: 32 AF XY: 0.0381 AC XY: 27673 AN XY: 726742

African (AFR) AF: 0.263 AC: 8801 AN: 33472

American (AMR) AF: 0.184 AC: 8192 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 1283 AN: 26130

East Asian (EAS) AF: 0.278 AC: 11018 AN: 39690

South Asian (SAS) AF: 0.0486 AC: 4190 AN: 86172

European-Finnish (FIN) AF: 0.0445 AC: 2347 AN: 52710

Middle Eastern (MID) AF: 0.0801 AC: 462 AN: 5768

European-Non Finnish (NFE) AF: 0.0156 AC: 17314 AN: 1111864

Other (OTH) AF: 0.0632 AC: 3819 AN: 60380

GnomAD4 genome AF: 0.108 AC: 16403 AN: 152048 Hom.: 1731 Cov.: 32 AF XY: 0.110 AC XY: 8147 AN XY: 74348

African (AFR) AF: 0.253 AC: 10459 AN: 41416

American (AMR) AF: 0.134 AC: 2046 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1531 AN: 5136

South Asian (SAS) AF: 0.0577 AC: 278 AN: 4816

European-Finnish (FIN) AF: 0.0472 AC: 501 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1197 AN: 68008

Other (OTH) AF: 0.0929 AC: 196 AN: 2110

Alfa AF: 0.0519 Hom.: 3194

Bravo AF: 0.125

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.245 AC: 1080

ESP6500EA AF: 0.0218 AC: 187

ExAC AF: 0.0841 AC: 10205

Asia WGS AF: 0.162 AC: 562 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0060	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.42	.;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.066
Sift	Benign	0.14	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.061	B;B
Vest4		0.047
MPC		0.097
ClinPred		0.0047	T
GERP RS		1.1
Varity_R		0.14
gMVP		0.64
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2499953; hg19: chr11-5010905; COSMIC: COSV56171936;