Genetic Variant LEMD2:c.1258+33G>C (chr6-33777105-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_181336.4(LEMD2):c.1258+33G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,610,032 control chromosomes in the GnomAD database, including 131,112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.38 ( 11383 hom., cov: 33)

Exomes 𝑓: 0.40 ( 119729 hom. )

Consequence

LEMD2
NM_181336.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.154

Publications

6 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cataract 46 juvenile-onset
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-33777105-C-G is Benign according to our data. Variant chr6-33777105-C-G is described in ClinVar as Benign. ClinVar VariationId is 1263137.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LEMD2	NM_181336.4	MANE Select	c.1258+33G>C	intron	N/A	NP_851853.1	Q8NC56-1
LEMD2	NM_001348710.2		c.859+33G>C	intron	N/A	NP_001335639.1
LEMD2	NM_001143944.1		c.352+33G>C	intron	N/A	NP_001137416.1	Q8NC56-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LEMD2	ENST00000293760.10	TSL:1 MANE Select	c.1258+33G>C	intron	N/A	ENSP00000293760.5	Q8NC56-1
LEMD2	ENST00000510598.5	TSL:1	n.448+33G>C	intron	N/A
LEMD2	ENST00000967488.1		c.1276+33G>C	intron	N/A	ENSP00000637547.1

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57147

AN:

151994

Hom.:

11381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.442

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.771

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.364

GnomAD2 exomes

AF:

0.424

AC:

106648

AN:

251408

AF XY:

0.434

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.355

Gnomad EAS exome

AF:

0.784

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.382

GnomAD4 exome

AF:

0.397

AC:

578538

AN:

1457920

Hom.:

119729

Cov.:

AF XY:

0.403

AC XY:

292316

AN XY:

725604

show subpopulations

African (AFR)

AF:

0.299

AC:

9990

AN:

33400

American (AMR)

AF:

0.353

AC:

15785

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

9392

AN:

26108

East Asian (EAS)

AF:

0.736

AC:

29221

AN:

39678

South Asian (SAS)

AF:

0.581

AC:

50060

AN:

86206

European-Finnish (FIN)

AF:

0.409

AC:

21836

AN:

53400

Middle Eastern (MID)

AF:

0.354

AC:

2037

AN:

5762

European-Non Finnish (NFE)

AF:

0.375

AC:

416181

AN:

1108388

Other (OTH)

AF:

0.399

AC:

24036

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

20331

40662

60993

81324

101655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13352

26704

40056

53408

66760

<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:

0.376

AC:

57165

AN:

152112

Hom.:

11383

Cov.:

AF XY:

0.381

AC XY:

28312

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.306

AC:

12690

AN:

41498

American (AMR)

AF:

0.349

AC:

5335

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

1284

AN:

3470

East Asian (EAS)

AF:

0.771

AC:

3980

AN:

5160

South Asian (SAS)

AF:

0.602

AC:

2905

AN:

4828

European-Finnish (FIN)

AF:

0.414

AC:

4384

AN:

10582

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.372

AC:

25283

AN:

67976

Other (OTH)

AF:

0.370

AC:

782

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1852

3704

5556

7408

9260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

562

1124

1686

2248

2810

<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:

0.363

Hom.:

1848

Bravo

AF:

0.367

Asia WGS

AF:

0.620

AC:

2157

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.24

(source)

DANN

Benign

0.36

PhyloP100

-0.15

PromoterAI

-0.018

Neutral

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over