rs121912497

Positions:

chr19-2435152-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032737.4(LMNB2):c.704G>A(p.Arg235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,603,552 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 12 hom., cov: 33)

Exomes 𝑓: 0.013 ( 176 hom. )

Consequence

LMNB2
NM_032737.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:2

Conservation

PhyloP100: 1.85

Variant links:

Genes affected

LMNB2 (HGNC:6638): (lamin B2) This gene encodes a B type nuclear lamin. The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Mutations in this gene are associated with acquired partial lipodystrophy. [provided by RefSeq, May 2012]

LMNB2 links:

LMNB2 (HGNC:):

LMNB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012448013).

BP6

Variant 19-2435152-C-T is Benign according to our data. Variant chr19-2435152-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 14474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNB2	NM_032737.4 linkuse as main transcript	c.704G>A	p.Arg235Gln	missense_variant	5/12	ENST00000325327.4	NP_116126.3	Q03252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LMNB2	ENST00000325327.4 linkuse as main transcript	c.704G>A	p.Arg235Gln	missense_variant	5/12	1	NM_032737.4	ENSP00000327054.3	Q03252
LMNB2	ENST00000527409.1 linkuse as main transcript	n.340G>A		non_coding_transcript_exon_variant	2/4	5
LMNB2	ENST00000534495.1 linkuse as main transcript	n.342G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.00977

AC:

1487

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0111

AC:

2621

AN:

235984

Hom.:

AF XY:

0.0112

AC XY:

1449

AN XY:

129544

show subpopulations

Gnomad AFR exome

AF:

0.00346

Gnomad AMR exome

AF:

0.00548

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00341

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.0134

AC:

19441

AN:

1451226

Hom.:

176

Cov.:

AF XY:

0.0131

AC XY:

9493

AN XY:

722336

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00553

Gnomad4 ASJ exome

AF:

0.0289

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00346

Gnomad4 FIN exome

AF:

0.0154

Gnomad4 NFE exome

AF:

0.0150

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.00976

AC:

1487

AN:

152326

Hom.:

Cov.:

AF XY:

0.00940

AC XY:

700

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.0323

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00954

Hom.:

Bravo

AF:

0.00932

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0139

AC:

119

ExAC

AF:

0.0113

AC:

1358

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	LMNB2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Acquired partial lipodystrophy

Benign:1Other:1

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg235Gln variant in LMNB2 has been identified in 2 individuals with acquired partial lipodystrophy (PMID: 16826530), but has also been identified in >1% of European (non-Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Acquired partial lipodistrophy is not known to be a Mendelian genetic disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for acquired partial lipodystrophy. -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -

Lipodystrophy, partial, acquired, susceptibility to;C4225289:Progressive myoclonic epilepsy type 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Lipodystrophy, partial, acquired, susceptibility to;C4225289:Progressive myoclonic epilepsy type 9;C5543051:Microcephaly 27, primary, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

May 26, 2022

This variant has been reported in the literature in at least 2 individuals with acquired partial lipodystrophy as well as 1 individual with familial partial lipodystrophy (Hegele 2006 PMID:16826530, Akinci 2017 PMID:28641778). This variant is present in the Genome Aggregation Database (Highest reported MAF 1.5% (160/10626) including 3 homozygotes (https://gnomad.broadinstitute.org/variant/19-2435152-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:14474). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Progressive myoclonic epilepsy type 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.011

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.42

REVEL

Uncertain

0.31

Sift4G

Benign

0.24

Vest4

0.66

MPC

0.49

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.067

gMVP

0.036

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over