Genetic Variant LEMD2:p.Leu13Pro (chr6-33789079-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_181336.4(LEMD2):c.38T>C(p.Leu13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,389,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LEMD2
NM_181336.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.81

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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-33789079-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 235192.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

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	HGVSp	Effect	Exon Rank	Protein
LEMD2	NM_181336.4	MANE Select	c.38T>C	p.Leu13Pro	missense	Exon 1 of 9	NP_851853.1
LEMD2	NM_001348710.2		c.38T>C	p.Leu13Pro	missense	Exon 1 of 9	NP_001335639.1
LEMD2	NM_001348709.2		c.-475T>C		5_prime_UTR	Exon 1 of 9	NP_001335638.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LEMD2	ENST00000293760.10	TSL:1 MANE Select	c.38T>C	p.Leu13Pro	missense	Exon 1 of 9	ENSP00000293760.5
LEMD2	ENST00000967488.1		c.38T>C	p.Leu13Pro	missense	Exon 1 of 9	ENSP00000637547.1
LEMD2	ENST00000967487.1		c.38T>C	p.Leu13Pro	missense	Exon 1 of 8	ENSP00000637546.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1389186

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28790

American (AMR)

AF:

0.00

AC:

AN:

35644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24372

East Asian (EAS)

AF:

0.00

AC:

AN:

32098

South Asian (SAS)

AF:

0.00

AC:

AN:

80086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4796

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085888

Other (OTH)

AF:

0.0000175

AC:

AN:

57268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.4

PhyloP100

2.8

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.82

Gain of disorder (P = 0.0134)

MVP

0.95

MPC

3.1

ClinPred

1.0

GERP RS

4.0

PromoterAI

0.068

Neutral

(source)

Varity_R

0.97

gMVP

0.91

Mutation Taster

=50/50

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over