chr6-33772710-G-A

Position:

chr6-33772710-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181336.4(LEMD2):c.1430C>T(p.Thr477Met) variant causes a missense change. The variant allele was found at a frequency of 0.000823 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 0 hom. )

Consequence

LEMD2
NM_181336.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17991751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LEMD2	NM_181336.4 linkuse as main transcript	c.1430C>T	p.Thr477Met	missense_variant	9/9	ENST00000293760.10
LEMD2	NM_001348710.2 linkuse as main transcript	c.1031C>T	p.Thr344Met	missense_variant	9/9
LEMD2	NM_001143944.1 linkuse as main transcript	c.524C>T	p.Thr175Met	missense_variant	8/8
LEMD2	NM_001348709.2 linkuse as main transcript	c.524C>T	p.Thr175Met	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEMD2	ENST00000293760.10 linkuse as main transcript	c.1430C>T	p.Thr477Met	missense_variant	9/9	1	NM_181336.4	P1	Q8NC56-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000343

AC:

AN:

250846

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000671

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000859

AC:

1255

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000479

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1430C>T (p.T477M) alteration is located in exon 9 (coding exon 9) of the LEMD2 gene. This alteration results from a C to T substitution at nucleotide position 1430, causing the threonine (T) at amino acid position 477 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cataract 46 juvenile-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Jul 23, 2021

The p.Thr477Metvariant in the LEMD2gene has not been previously reported in association with disease. This variant has been identified in 84/128,664 European non-Finnishchromosomesincluding 1 homozygote (97/282,248 chromosomes overall)by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The threonine at position 477 is well conserved in mammals. Computational tools predict that the p.Thr477Metvariant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Thr477Met variant is uncertain;however, population frequency data suggests that this variant is more likely to be benign than pathogenic. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PP3; BS1_Supporting] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.4

.;M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

D;D;.;D

REVEL

Uncertain

0.43

Sift

Benign

0.077

T;D;.;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.63, 0.68, 0.75

MVP

0.45

MPC

1.6

ClinPred

0.15

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.88

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