1-225422182-A-G

Variant names:

• chr1-225422182-A-G
• rs1056608
• NM_002296.4:c.261T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002296.4(LBR):​c.261T>C​(p.Pro87Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,613,514 control chromosomes in the GnomAD database, including 482,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38108 hom., cov: 31)
  • Exomes 𝑓: 0.78 (444240 hom.)
• Consequence: LBR NM_002296.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.786

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-225422182-A-G is Benign according to our data. Variant chr1-225422182-A-G is described in ClinVar as [Benign]. Clinvar id is 258617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225422182-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.261T>C	p.Pro87Pro	synonymous_variant	Exon 3 of 14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.261T>C	p.Pro87Pro	synonymous_variant	Exon 3 of 14	1	NM_002296.4	ENSP00000272163.4

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103922 AN: 151922 Hom.: 38101 Cov.: 31

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.838

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.732

GnomAD3 exomes AF: 0.763 AC: 191794 AN: 251336 Hom.: 75032 AF XY: 0.761 AC XY: 103411 AN XY: 135852

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.863

Gnomad EAS exome AF: 0.897

Gnomad SAS exome AF: 0.656

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.787

Gnomad OTH exome AF: 0.795

GnomAD4 exome AF: 0.776 AC: 1133824 AN: 1461474 Hom.: 444240 Cov.: 56 AF XY: 0.773 AC XY: 562047 AN XY: 727020

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.844

Gnomad4 ASJ exome AF: 0.859

Gnomad4 EAS exome AF: 0.908

Gnomad4 SAS exome AF: 0.652

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.788

Gnomad4 OTH exome AF: 0.775

GnomAD4 genome AF: 0.684 AC: 103960 AN: 152040 Hom.: 38108 Cov.: 31 AF XY: 0.684 AC XY: 50812 AN XY: 74300

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.856

Gnomad4 EAS AF: 0.893

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.774

Gnomad4 NFE AF: 0.791

Gnomad4 OTH AF: 0.728

Alfa AF: 0.769 Hom.: 14721

Bravo AF: 0.678

Asia WGS AF: 0.747 AC: 2598 AN: 3478

EpiCase AF: 0.797

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 75% of total chromosomes in ExAC -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Greenberg dysplasia Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Reynolds syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pelger-Huët anomaly Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.2
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1056608; hg19: chr1-225609884;