6-33776996-C-G

Position:

• chr6-33776996-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181336.4(LEMD2):​c.1319G>C​(p.Gly440Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LEMD2 NM_181336.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.288817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEMD2	NM_181336.4	c.1319G>C	p.Gly440Ala	missense_variant	8/9	ENST00000293760.10	NP_851853.1
LEMD2	NM_001348710.2	c.920G>C	p.Gly307Ala	missense_variant	8/9		NP_001335639.1
LEMD2	NM_001143944.1	c.413G>C	p.Gly138Ala	missense_variant	7/8		NP_001137416.1
LEMD2	NM_001348709.2	c.413G>C	p.Gly138Ala	missense_variant	8/9		NP_001335638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEMD2	ENST00000293760.10	c.1319G>C	p.Gly440Ala	missense_variant	8/9	1	NM_181336.4	ENSP00000293760.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.1319G>C (p.G440A) alteration is located in exon 8 (coding exon 8) of the LEMD2 gene. This alteration results from a G to C substitution at nucleotide position 1319, causing the glycine (G) at amino acid position 440 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;M;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.020	N;N;.;N
REVEL	Benign	0.23
Sift	Benign	0.95	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.50, 0.50, 0.51
MutPred		0.46		.;Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.55
MPC		1.5
ClinPred		0.69	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.86

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

Other links and lift over

dbSNP: rs1767444862; hg19: chr6-33744773;