chr6-33789079-A-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_181336.4(LEMD2):​c.38T>C​(p.Leu13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,389,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L13R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LEMD2 NM_181336.4 missense
• Clinical Significance: Not reported in ClinVar
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-33789079-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEMD2	NM_181336.4	c.38T>C	p.Leu13Pro	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>C	p.Leu13Pro	missense_variant	Exon 1 of 9	1	NM_181336.4	ENSP00000293760.5
LEMD2	ENST00000421671.6	n.38T>C		non_coding_transcript_exon_variant	Exon 1 of 9	3		ENSP00000398733.2
LEMD2	ENST00000442696.6	c.-251T>C		upstream_gene_variant		5		ENSP00000408524.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1389186 Hom.: 0 Cov.: 33 AF XY: 0.00000289 AC XY: 2 AN XY: 691318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	.;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.81
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 = 0.0134);Gain of disorder (P = 0.0134);
MVP		0.95
MPC		3.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33756856;