Genetic Variant NM_032737.4:c.1244C>A (chr19-2434064-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032737.4(LMNB2):c.1244C>A(p.Ser415*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,314 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. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LMNB2
NM_032737.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 27, primary, autosomal dominant
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
progressive myoclonic epilepsy type 9
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
microcephaly
Inheritance: AD Classification: MODERATE Submitted by: Franklin by Genoox
lipodystrophy, partial, acquired, susceptibility to
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
central nervous system malformation
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LMNB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNB2	NM_032737.4 link	c.1244C>A	p.Ser415*	stop_gained	Exon 8 of 12	ENST00000325327.4	NP_116126.3	Q03252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMNB2	ENST00000325327.4 link	c.1244C>A	p.Ser415*	stop_gained	Exon 8 of 12	1	NM_032737.4	ENSP00000327054.3	Q03252
LMNB2	ENST00000490554.5 link	n.435C>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
LMNB2	ENST00000532465.1 link	n.-165C>A		upstream_gene_variant		3
LMNB2	ENST00000527409.1 link	n.*231C>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446314

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718600

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

42406

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.00

AC:

AN:

84956

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106116

Other (OTH)

AF:

0.00

AC:

AN:

59748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

PhyloP100

7.3

Vest4

0.093

GERP RS

4.2

Mutation Taster

=0/200

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over