rs2296744

Variant names:

• chr6-33772605-G-A
• rs2296744
• NM_181336.4:c.*23C>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.*23C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 1,604,308 control chromosomes in the GnomAD database, including 235,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (17677 hom., cov: 34)
  • Exomes 𝑓: 0.54 (218134 hom.)
• Consequence: LEMD2 NM_181336.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.749
• Publications: 17 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• cataract 46 juvenile-onset

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.77).
• BP6: Variant 6-33772605-G-A is Benign according to our data. Variant chr6-33772605-G-A is described in ClinVar as Benign. ClinVar VariationId is 1289212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEMD2	NM_181336.4	c.*23C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000293760.10	NP_851853.1
LEMD2	NM_001348710.2	c.*23C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001335639.1
LEMD2	NM_001143944.1	c.*23C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001137416.1
LEMD2	NM_001348709.2	c.*23C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001335638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEMD2	ENST00000293760.10	c.*23C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_181336.4	ENSP00000293760.5

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69408 AN: 152044 Hom.: 17669 Cov.: 34

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.535 AC: 130642 AN: 244046 AF XY: 0.546

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.543 AC: 788243 AN: 1452146 Hom.: 218134 Cov.: 36 AF XY: 0.546 AC XY: 394269 AN XY: 721596

African (AFR) AF: 0.217 AC: 7252 AN: 33366

American (AMR) AF: 0.472 AC: 20864 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 13907 AN: 25562

East Asian (EAS) AF: 0.795 AC: 31452 AN: 39576

South Asian (SAS) AF: 0.599 AC: 50858 AN: 84862

European-Finnish (FIN) AF: 0.533 AC: 28086 AN: 52652

Middle Eastern (MID) AF: 0.505 AC: 2889 AN: 5726

European-Non Finnish (NFE) AF: 0.543 AC: 601063 AN: 1106186

Other (OTH) AF: 0.531 AC: 31872 AN: 59996

GnomAD4 genome AF: 0.456 AC: 69421 AN: 152162 Hom.: 17677 Cov.: 34 AF XY: 0.457 AC XY: 33977 AN XY: 74392

African (AFR) AF: 0.224 AC: 9318 AN: 41522

American (AMR) AF: 0.460 AC: 7032 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1882 AN: 3470

East Asian (EAS) AF: 0.781 AC: 4044 AN: 5180

South Asian (SAS) AF: 0.607 AC: 2918 AN: 4810

European-Finnish (FIN) AF: 0.536 AC: 5675 AN: 10578

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36842 AN: 68004

Other (OTH) AF: 0.483 AC: 1018 AN: 2108

Alfa AF: 0.489 Hom.: 3858

Bravo AF: 0.442

Asia WGS AF: 0.622 AC: 2167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		0.75
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: rs2296744; hg19: chr6-33740382; COSMIC: COSV53393268; COSMIC: COSV53393268;