rs2230419

Variant names:

• chr1-225419442-C-A
• rs2230419
• NM_002296.4:c.461G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-225419442-C-A
• chr1-225419442-C-G
• chr1-225419442-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002296.4(LBR):​c.461G>T​(p.Ser154Ile) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S154N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167
• Publications: 42 publications found

Genes affected

LBR (HGNC:6518): (lamin B receptor) The protein encoded by this gene belongs to the ERG4/ERG24 family. It localized in the nuclear envelope inner membrane and anchors the lamina and the heterochromatin to the membrane. It may mediate interaction between chromatin and lamin B. Mutations of this gene has been associated with autosomal recessive HEM/Greenberg skeletal dysplasia. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

LBR Gene-Disease associations (from GenCC):

• Greenberg dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Pelger-Huet anomaly

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• regressive spondylometaphyseal dysplasia

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041336507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.461G>T	p.Ser154Ile	missense_variant	Exon 5 of 14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.461G>T	p.Ser154Ile	missense_variant	Exon 5 of 14	1	NM_002296.4	ENSP00000272163.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.030
DANN	Benign	0.43
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.092	.;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-1.6	N;N;.
PhyloP100		-0.17
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.49	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.038
MutPred		0.26		Loss of phosphorylation at S154 (P = 0.0467);Loss of phosphorylation at S154 (P = 0.0467);Loss of phosphorylation at S154 (P = 0.0467);
MVP		0.36
MPC		0.12
ClinPred		0.029	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.26
Mutation Taster		=94/6	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: rs2230419; hg19: chr1-225607144;