chr6-33789079-A-C

Variant names:

• chr6-33789079-A-C
• rs878852983
• NM_181336.4:c.38T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.81

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 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	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	Appris	UniProt
LEMD2	ENST00000293760.10	c.38T>G	p.Leu13Arg	missense_variant	Exon 1 of 9	1	NM_181336.4	ENSP00000293760.5
LEMD2	ENST00000421671.6	n.38T>G		non_coding_transcript_exon_variant	Exon 1 of 9	3		ENSP00000398733.2
LEMD2	ENST00000442696.6	c.-251T>G		upstream_gene_variant		5		ENSP00000408524.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.80	.;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.91	D
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	D
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

Other links and lift over

dbSNP: rs878852983; hg19: chr6-33756856;