Genetic Variant LEMD2:p.His360Pro (chr6-33778319-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181336.4(LEMD2):c.1079A>C(p.His360Pro) 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 benign outcome for this variant. 14/21 in silico tools predict a benign 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. H360R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LEMD2
NM_181336.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.537

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: 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16204831).

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	UniProt
LEMD2	NM_181336.4	MANE Select	c.1079A>C	p.His360Pro	missense	Exon 6 of 9	NP_851853.1	Q8NC56-1
LEMD2	NM_001348710.2		c.680A>C	p.His227Pro	missense	Exon 6 of 9	NP_001335639.1
LEMD2	NM_001143944.1		c.173A>C	p.His58Pro	missense	Exon 5 of 8	NP_001137416.1	Q8NC56-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LEMD2	ENST00000293760.10	TSL:1 MANE Select	c.1079A>C	p.His360Pro	missense	Exon 6 of 9	ENSP00000293760.5	Q8NC56-1
LEMD2	ENST00000510598.5	TSL:1	n.269A>C		non_coding_transcript_exon	Exon 2 of 5
LEMD2	ENST00000967488.1		c.1097A>C	p.His366Pro	missense	Exon 6 of 9	ENSP00000637547.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.0045

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.42

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.64

M_CAP

Benign

0.0073

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.54

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.11

Sift

Uncertain

0.014

Sift4G

Uncertain

0.021

Polyphen

0.11

Vest4

0.31

MutPred

0.38

Gain of glycosylation at H360 (P = 0.0242)

MVP

0.51

MPC

1.0

ClinPred

0.18

GERP RS

2.7

PromoterAI

0.011

Neutral

(source)

Varity_R

0.40

gMVP

0.96

Mutation Taster

=97/3

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over