6-33778319-T-C

Variant names:

• chr6-33778319-T-C
• rs1582255510
• NM_181336.4:c.1079A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181336.4(LEMD2):​c.1079A>G​(p.His360Arg) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEMD2 NM_181336.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537
• Publications: 0 publications found

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

ACMG classification

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=0.070240766).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEMD2	NM_181336.4	MANE Select	c.1079A>G	p.His360Arg	missense	Exon 6 of 9	NP_851853.1	Q8NC56-1
	LEMD2	NM_001348710.2		c.680A>G	p.His227Arg	missense	Exon 6 of 9	NP_001335639.1
	LEMD2	NM_001143944.1		c.173A>G	p.His58Arg	missense	Exon 5 of 8	NP_001137416.1	Q8NC56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEMD2	ENST00000293760.10	TSL:1 MANE Select	c.1079A>G	p.His360Arg	missense	Exon 6 of 9	ENSP00000293760.5	Q8NC56-1
	LEMD2	ENST00000510598.5	TSL:1	n.269A>G		non_coding_transcript_exon	Exon 2 of 5
	LEMD2	ENST00000967488.1		c.1097A>G	p.His366Arg	missense	Exon 6 of 9	ENSP00000637547.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.26
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.54
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.30		Gain of methylation at H360 (P = 0.0486)
MVP		0.48
MPC		0.71
ClinPred		0.015	T
GERP RS		2.7
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.77
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1582255510; hg19: chr6-33746096;