dbSNP rs878852983: LEMD2:p.Leu13Arg (chr6-33789079-A-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_181336.4(LEMD2):c.38T>G(p.Leu13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

LEMD2
NM_181336.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.81

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 6-33789079-A-C is Pathogenic according to our data. Variant chr6-33789079-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 235192.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-33789079-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEMD2	NM_181336.4 link	c.38T>G	p.Leu13Arg	missense_variant	Exon 1 of 9	ENST00000293760.10	NP_851853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LEMD2	ENST00000293760.10 link	c.38T>G	p.Leu13Arg	missense_variant	Exon 1 of 9	1	NM_181336.4	ENSP00000293760.5	Q8NC56-1
LEMD2	ENST00000421671.6 link	n.38T>G		non_coding_transcript_exon_variant	Exon 1 of 9	3		ENSP00000398733.2	D6RBV0
LEMD2	ENST00000442696.6 link	c.-251T>G		upstream_gene_variant		5		ENSP00000408524.2	H7C2Z0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 46 juvenile-onset

Pathogenic:2

Nov 01, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant co-segregates with juvenile cataracts in 39 family members (including 17 affected individuals [homozygous], 22 obligate carriers) across multiple sibships within a large Hutterite population. A potential association with sudden cardiac death is also observed. -

Feb 13, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.80

.;T

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.82

Gain of disorder (P = 0.0154);Gain of disorder (P = 0.0154);

MVP

0.95

MPC

3.0

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.97

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over