NM_181336.4:c.1361+9C>T

Variant names:

• chr6-33776945-G-A
• rs112565654
• NM_181336.4:c.1361+9C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_181336.4(LEMD2):​c.1361+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,611,084 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (13 hom.)
• Consequence: LEMD2 NM_181336.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.47
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-33776945-G-A is Benign according to our data. Variant chr6-33776945-G-A is described in ClinVar as Benign. ClinVar VariationId is 1537072.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.1361+9C>T		intron	N/A	NP_851853.1	Q8NC56-1
	LEMD2	NM_001348710.2		c.962+9C>T		intron	N/A	NP_001335639.1
	LEMD2	NM_001143944.1		c.455+9C>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.1361+9C>T		intron	N/A	ENSP00000293760.5	Q8NC56-1
	LEMD2	ENST00000510598.5	TSL:1	n.551+9C>T		intron	N/A
	LEMD2	ENST00000504692.1	TSL:3	c.*5C>T		3_prime_UTR	Exon 3 of 3	ENSP00000421112.1	H0Y8H8

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 716 AN: 152202 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00204 AC: 512 AN: 250896 AF XY: 0.00174

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00116 AC: 1695 AN: 1458764 Hom.: 13 Cov.: 32 AF XY: 0.00115 AC XY: 834 AN XY: 725864

African (AFR) AF: 0.0149 AC: 499 AN: 33412

American (AMR) AF: 0.00295 AC: 132 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86150

European-Finnish (FIN) AF: 0.000207 AC: 11 AN: 53232

Middle Eastern (MID) AF: 0.00517 AC: 25 AN: 4840

European-Non Finnish (NFE) AF: 0.000774 AC: 859 AN: 1110396

Other (OTH) AF: 0.00204 AC: 123 AN: 60218

GnomAD4 genome AF: 0.00475 AC: 724 AN: 152320 Hom.: 5 Cov.: 33 AF XY: 0.00452 AC XY: 337 AN XY: 74486

African (AFR) AF: 0.0133 AC: 553 AN: 41566

American (AMR) AF: 0.00470 AC: 72 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68030

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00243 Hom.: 1

Bravo AF: 0.00561

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00196

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	-0.84
CADD	Benign	1.2
DANN	Benign	0.79
PhyloP100		-3.5
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs112565654; hg19: chr6-33744722;