NM_002345.4:c.507T>C

Variant names:

• chr12-91108473-A-G
• rs17853500
• NM_002345.4:c.507T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002345.4(LUM):​c.507T>C​(p.Asn169Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,614,026 control chromosomes in the GnomAD database, including 2,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (250 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1873 hom.)
• Consequence: LUM NM_002345.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05
• Publications: 12 publications found

Genes affected

LUM (HGNC:6724): (lumican) This gene encodes a member of the small leucine-rich proteoglycan (SLRP) family that includes decorin, biglycan, fibromodulin, keratocan, epiphycan, and osteoglycin. In these bifunctional molecules, the protein moiety binds collagen fibrils and the highly charged hydrophilic glycosaminoglycans regulate interfibrillar spacings. Lumican is the major keratan sulfate proteoglycan of the cornea but is also distributed in interstitial collagenous matrices throughout the body. Lumican may regulate collagen fibril organization and circumferential growth, corneal transparency, and epithelial cell migration and tissue repair. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-91108473-A-G is Benign according to our data. Variant chr12-91108473-A-G is described in ClinVar as Benign. ClinVar VariationId is 1275250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LUM	NM_002345.4	c.507T>C	p.Asn169Asn	synonymous_variant	Exon 2 of 3	ENST00000266718.5	NP_002336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LUM	ENST00000266718.5	c.507T>C	p.Asn169Asn	synonymous_variant	Exon 2 of 3	1	NM_002345.4	ENSP00000266718.4
LUM	ENST00000546642.1	n.257T>C		non_coding_transcript_exon_variant	Exon 2 of 3	3
LUM	ENST00000548071.1	n.90-190T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4739 AN: 152086 Hom.: 249 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0522 AC: 13094 AN: 250934 AF XY: 0.0522

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0568

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0306 AC: 44767 AN: 1461822 Hom.: 1873 Cov.: 33 AF XY: 0.0319 AC XY: 23209 AN XY: 727210

African (AFR) AF: 0.0133 AC: 444 AN: 33480

American (AMR) AF: 0.0556 AC: 2488 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 455 AN: 26136

East Asian (EAS) AF: 0.232 AC: 9214 AN: 39678

South Asian (SAS) AF: 0.0817 AC: 7043 AN: 86258

European-Finnish (FIN) AF: 0.0246 AC: 1312 AN: 53420

Middle Eastern (MID) AF: 0.0321 AC: 185 AN: 5766

European-Non Finnish (NFE) AF: 0.0191 AC: 21194 AN: 1111968

Other (OTH) AF: 0.0403 AC: 2432 AN: 60392

GnomAD4 genome AF: 0.0312 AC: 4744 AN: 152204 Hom.: 250 Cov.: 32 AF XY: 0.0344 AC XY: 2561 AN XY: 74418

African (AFR) AF: 0.0156 AC: 650 AN: 41544

American (AMR) AF: 0.0396 AC: 605 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1347 AN: 5162

South Asian (SAS) AF: 0.0909 AC: 438 AN: 4818

European-Finnish (FIN) AF: 0.0198 AC: 210 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0197 AC: 1343 AN: 68010

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0208 Hom.: 21

Bravo AF: 0.0323

Asia WGS AF: 0.169 AC: 586 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

LUM-related disorder Benign:1

Feb 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.8
DANN	Benign	0.40
PhyloP100		1.0
Mutation Taster		=100/0	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: rs17853500; hg19: chr12-91502250; COSMIC: COSV57127703;