Genetic Variant LEMD2:p.Gln306Arg (chr6-33781090-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_181336.4(LEMD2):c.917A>G(p.Gln306Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,612,020 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 3 hom. )

Consequence

LEMD2
NM_181336.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.986

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005554527).

BP6

Variant 6-33781090-T-C is Benign according to our data. Variant chr6-33781090-T-C is described in ClinVar as Benign. ClinVar VariationId is 2053297.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEMD2	NM_181336.4 link	c.917A>G	p.Gln306Arg	missense_variant	Exon 4 of 9	ENST00000293760.10	NP_851853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEMD2	ENST00000293760.10 link	c.917A>G	p.Gln306Arg	missense_variant	Exon 4 of 9	1	NM_181336.4	ENSP00000293760.5		Q8NC56-1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00158

AC:

397

AN:

251062

AF XY:

0.00125

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000323

AC:

471

AN:

1459668

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

726320

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33446

American (AMR)

AF:

0.0102

AC:

455

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110098

Other (OTH)

AF:

0.000149

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000440

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41588

American (AMR)

AF:

0.00366

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000211

Hom.:

Bravo

AF:

0.000831

ExAC

AF:

0.00136

AC:

165

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.082

T;T;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.63

.;T;T;T

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.

PhyloP100

0.99

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.33

N;.;N;N

REVEL

Benign

0.029

Sift

Benign

0.50

T;.;T;T

Sift4G

Benign

0.41

T;T;T;.

Polyphen

0.0070

B;B;.;.

Vest4

0.22

MVP

0.41

MPC

0.64

ClinPred

0.013

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.61

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over