rs2230419

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002296.4(LBR):​c.461G>A​(p.Ser154Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,609,378 control chromosomes in the GnomAD database, including 543,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (43287 hom., cov: 33)
  • Exomes 𝑓: 0.82 (500696 hom.)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.891029E-7).
• BP6: Variant 1-225419442-C-T is Benign according to our data. Variant chr1-225419442-C-T is described in ClinVar as Benign. ClinVar VariationId is 258619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002296.4. 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
	LBR	NM_002296.4	MANE Select	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	NP_002287.2
	LBR	NM_194442.3		c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	NP_919424.1	Q14739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	ENST00000272163.9	TSL:1 MANE Select	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000272163.4	Q14739
	LBR	ENST00000338179.6	TSL:5	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000339883.2	Q14739
	LBR	ENST00000885795.1		c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110920 AN: 152030 Hom.: 43266 Cov.: 33

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.781

GnomAD2 exomes AF: 0.811 AC: 202788 AN: 249900 AF XY: 0.810

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.872

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.958

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.838

Gnomad OTH exome AF: 0.850

GnomAD4 exome AF: 0.825 AC: 1202186 AN: 1457230 Hom.: 500696 Cov.: 34 AF XY: 0.822 AC XY: 596356 AN XY: 725214

African (AFR) AF: 0.411 AC: 13705 AN: 33386

American (AMR) AF: 0.869 AC: 38793 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23204 AN: 26104

East Asian (EAS) AF: 0.962 AC: 38185 AN: 39688

South Asian (SAS) AF: 0.698 AC: 60009 AN: 86030

European-Finnish (FIN) AF: 0.858 AC: 45803 AN: 53376

Middle Eastern (MID) AF: 0.864 AC: 4914 AN: 5686

European-Non Finnish (NFE) AF: 0.837 AC: 927851 AN: 1108056

Other (OTH) AF: 0.825 AC: 49722 AN: 60252

GnomAD4 genome AF: 0.729 AC: 110989 AN: 152148 Hom.: 43287 Cov.: 33 AF XY: 0.732 AC XY: 54406 AN XY: 74374

African (AFR) AF: 0.428 AC: 17743 AN: 41460

American (AMR) AF: 0.850 AC: 12995 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3079 AN: 3470

East Asian (EAS) AF: 0.957 AC: 4957 AN: 5180

South Asian (SAS) AF: 0.698 AC: 3369 AN: 4824

European-Finnish (FIN) AF: 0.862 AC: 9138 AN: 10602

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57102 AN: 67998

Other (OTH) AF: 0.785 AC: 1659 AN: 2114

Alfa AF: 0.812 Hom.: 219363

Bravo AF: 0.718

TwinsUK AF: 0.830 AC: 3077

ALSPAC AF: 0.840 AC: 3238

ESP6500AA AF: 0.437 AC: 1926

ESP6500EA AF: 0.840 AC: 7221

ExAC AF: 0.799 AC: 97048

Asia WGS AF: 0.823 AC: 2862 AN: 3478

EpiCase AF: 0.844

EpiControl AF: 0.846

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Greenberg dysplasia (2)
-	-	2	not specified (2)
-	-	1	Pelger-Huët anomaly (1)
-	-	1	Reynolds syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.015
DANN	Benign	0.38
DEOGEN2	Benign	0.32	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.056	T
MetaRNN	Benign	9.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.17
Sift	Benign	0.56	T
Sift4G	Benign	0.54	T
Polyphen		0.014	B
Vest4		0.015
MPC		0.094
ClinPred		0.010	T
GERP RS		-8.0
Varity_R		0.030
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV55291160; COSMIC: COSV55291160;