Genetic Variant LEMD2:c.1362-37G>A (chr6-33772815-C-T) – 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.1362-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,590,830 control chromosomes in the GnomAD database, including 243,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.48 ( 19071 hom., cov: 33)

Exomes 𝑓: 0.55 ( 224154 hom. )

Consequence

LEMD2
NM_181336.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.39

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=-0.83).

BP6

Variant 6-33772815-C-T is Benign according to our data. Variant chr6-33772815-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279226.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 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.1362-37G>A	intron	N/A	NP_851853.1	Q8NC56-1
LEMD2	NM_001348710.2		c.963-37G>A	intron	N/A	NP_001335639.1
LEMD2	NM_001143944.1		c.456-37G>A	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.1362-37G>A	intron	N/A	ENSP00000293760.5	Q8NC56-1
LEMD2	ENST00000510598.5	TSL:1	n.552-37G>A	intron	N/A
LEMD2	ENST00000967488.1		c.1380-37G>A	intron	N/A	ENSP00000637547.1

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73459

AN:

151968

Hom.:

19066

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.567

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.816

Gnomad SAS

AF:

0.665

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.546

Gnomad OTH

AF:

0.506

GnomAD2 exomes

AF:

0.558

AC:

126538

AN:

226934

AF XY:

0.567

show subpopulations

Gnomad AFR exome

AF:

0.296

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.821

Gnomad FIN exome

AF:

0.533

Gnomad NFE exome

AF:

0.549

Gnomad OTH exome

AF:

0.543

GnomAD4 exome

AF:

0.553

AC:

796198

AN:

1438744

Hom.:

224154

Cov.:

AF XY:

0.558

AC XY:

398457

AN XY:

713960

show subpopulations

African (AFR)

AF:

0.288

AC:

9500

AN:

33006

American (AMR)

AF:

0.487

AC:

20863

AN:

42830

Ashkenazi Jewish (ASJ)

AF:

0.547

AC:

13779

AN:

25180

East Asian (EAS)

AF:

0.819

AC:

32086

AN:

39182

South Asian (SAS)

AF:

0.657

AC:

54942

AN:

83656

European-Finnish (FIN)

AF:

0.534

AC:

27613

AN:

51744

Middle Eastern (MID)

AF:

0.525

AC:

2913

AN:

5544

European-Non Finnish (NFE)

AF:

0.548

AC:

601988

AN:

1098184

Other (OTH)

AF:

0.547

AC:

32514

AN:

59418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

16130

32259

48389

64518

80648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17150

34300

51450

68600

85750

<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:

0.483

AC:

73483

AN:

152086

Hom.:

19071

Cov.:

AF XY:

0.484

AC XY:

35963

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.295

AC:

12250

AN:

41472

American (AMR)

AF:

0.480

AC:

7343

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1892

AN:

3466

East Asian (EAS)

AF:

0.817

AC:

4229

AN:

5178

South Asian (SAS)

AF:

0.665

AC:

3209

AN:

4822

European-Finnish (FIN)

AF:

0.536

AC:

5678

AN:

10584

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.546

AC:

37103

AN:

67956

Other (OTH)

AF:

0.510

AC:

1078

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1854

3709

5563

7418

9272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

668

1336

2004

2672

3340

<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:

0.502

Hom.:

3669

Bravo

AF:

0.472

Asia WGS

AF:

0.676

AC:

2353

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

-0.83

CADD

Benign

0.74

(source)

DANN

Benign

0.81

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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