Genetic Variant LEMD2:c.*380G>A (chr6-33772248-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181336.4(LEMD2):c.*380G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 172,768 control chromosomes in the GnomAD database, including 11,124 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 9655 hom., cov: 33)

Exomes 𝑓: 0.36 ( 1469 hom. )

Consequence

LEMD2
NM_181336.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

Publications

18 publications found

Variant links:

Genes affected

LEMD2 (HGNC:21244): (LEM domain nuclear envelope protein 2) This gene encodes a LEM domain-containing transmembrane protein of the inner nuclear membrane. The protein is involved in nuclear structure organization and plays a role in cell signaling and differentiation. Mutations in this gene result in Cataract 46, juvenile-onset. Multiple transcript variants have been found for this gene. [provided by RefSeq, Feb 2017]

LEMD2 Gene-Disease associations (from GenCC):

Marbach-Rustad progeroid syndrome
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
cataract 46 juvenile-onset
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
early-onset posterior subcapsular cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LEMD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
LEMD2	NM_181336.4 link	c.*380G>A	3_prime_UTR_variant	Exon 9 of 9	ENST00000293760.10	NP_851853.1
LEMD2	NM_001348710.2 link	c.*380G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001335639.1
LEMD2	NM_001143944.1 link	c.*380G>A	3_prime_UTR_variant	Exon 8 of 8		NP_001137416.1
LEMD2	NM_001348709.2 link	c.*380G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001335638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEMD2	ENST00000293760.10 link	c.*380G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_181336.4	ENSP00000293760.5		Q8NC56-1

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50833

AN:

151984

Hom.:

9652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.439

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.543

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.327

GnomAD4 exome

AF:

0.356

AC:

7361

AN:

20666

Hom.:

1469

Cov.:

AF XY:

0.365

AC XY:

3889

AN XY:

10664

show subpopulations

African (AFR)

AF:

0.164

AC:

AN:

550

American (AMR)

AF:

0.321

AC:

340

AN:

1060

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

188

AN:

604

East Asian (EAS)

AF:

0.737

AC:

410

AN:

556

South Asian (SAS)

AF:

0.479

AC:

740

AN:

1544

European-Finnish (FIN)

AF:

0.381

AC:

509

AN:

1336

Middle Eastern (MID)

AF:

0.315

AC:

AN:

108

European-Non Finnish (NFE)

AF:

0.339

AC:

4626

AN:

13640

Other (OTH)

AF:

0.334

AC:

424

AN:

1268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

226

452

677

903

1129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.334

AC:

50842

AN:

152102

Hom.:

9655

Cov.:

AF XY:

0.339

AC XY:

25241

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.186

AC:

7741

AN:

41522

American (AMR)

AF:

0.314

AC:

4805

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1273

AN:

3468

East Asian (EAS)

AF:

0.751

AC:

3878

AN:

5164

South Asian (SAS)

AF:

0.544

AC:

2620

AN:

4818

European-Finnish (FIN)

AF:

0.413

AC:

4366

AN:

10574

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24952

AN:

67960

Other (OTH)

AF:

0.331

AC:

699

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1634

3269

4903

6538

8172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.348

Hom.:

7497

Bravo

AF:

0.320

Asia WGS

AF:

0.566

AC:

1971

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over