6-33777103-G-A

Variant names:

• chr6-33777103-G-A
• rs113782257
• NM_181336.4:c.1258+35C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_181336.4(LEMD2):​c.1258+35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,610,162 control chromosomes in the GnomAD database, including 703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (335 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (368 hom.)
• Consequence: LEMD2 NM_181336.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.31
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-33777103-G-A is Benign according to our data. Variant chr6-33777103-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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.1258+35C>T		intron	N/A	NP_851853.1	Q8NC56-1
	LEMD2	NM_001348710.2		c.859+35C>T		intron	N/A	NP_001335639.1
	LEMD2	NM_001143944.1		c.352+35C>T		intron	N/A	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.1258+35C>T		intron	N/A	ENSP00000293760.5	Q8NC56-1
	LEMD2	ENST00000510598.5	TSL:1	n.448+35C>T		intron	N/A
	LEMD2	ENST00000967488.1		c.1276+35C>T		intron	N/A	ENSP00000637547.1

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5472 AN: 152184 Hom.: 335 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0106 AC: 2673 AN: 251424 AF XY: 0.00793

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00441 AC: 6430 AN: 1457860 Hom.: 368 Cov.: 31 AF XY: 0.00382 AC XY: 2774 AN XY: 725608

African (AFR) AF: 0.139 AC: 4630 AN: 33402

American (AMR) AF: 0.00769 AC: 344 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 320 AN: 26104

East Asian (EAS) AF: 0.00222 AC: 88 AN: 39682

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86178

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00868 AC: 50 AN: 5760

European-Non Finnish (NFE) AF: 0.000365 AC: 405 AN: 1108332

Other (OTH) AF: 0.00899 AC: 542 AN: 60274

GnomAD4 genome AF: 0.0360 AC: 5482 AN: 152302 Hom.: 335 Cov.: 33 AF XY: 0.0348 AC XY: 2590 AN XY: 74472

African (AFR) AF: 0.122 AC: 5072 AN: 41554

American (AMR) AF: 0.0162 AC: 248 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68030

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0166 Hom.: 34

Bravo AF: 0.0418

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.038
DANN	Benign	0.46
PhyloP100		-2.3
PromoterAI		-0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs113782257; hg19: chr6-33744880;