19-2438464-G-A

Variant names:

• chr19-2438464-G-A
• rs797045143
• NM_032737.4:c.469C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000325327.4(LMNB2):​c.469C>T​(p.His157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LMNB2 ENST00000325327.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.10
• Publications: 7 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 19-2438464-G-A is Pathogenic according to our data. Variant chr19-2438464-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208980.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000325327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB2	NM_032737.4	MANE Select	c.469C>T	p.His157Tyr	missense	Exon 3 of 12	NP_116126.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB2	ENST00000325327.4	TSL:1 MANE Select	c.469C>T	p.His157Tyr	missense	Exon 3 of 12	ENSP00000327054.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Progressive myoclonic epilepsy type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.57	T
PhyloP100		2.1
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.18
Sift4G	Benign	0.15	T
Vest4		0.84
MVP		0.28
MPC		0.79
ClinPred		0.91	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.18
gMVP		0.064
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs797045143; hg19: chr19-2438462;