chr1-225422182-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000272163.9(LBR):​c.261T>G​(p.Pro87Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P87P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: LBR ENST00000272163.9 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• Publications: 23 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000272163.9. 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
	LBR	NM_002296.4	MANE Select	c.261T>G	p.Pro87Pro	synonymous	Exon 3 of 14	NP_002287.2
	LBR	NM_194442.3		c.261T>G	p.Pro87Pro	synonymous	Exon 3 of 14	NP_919424.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	ENST00000272163.9	TSL:1 MANE Select	c.261T>G	p.Pro87Pro	synonymous	Exon 3 of 14	ENSP00000272163.4
	LBR	ENST00000338179.6	TSL:5	c.261T>G	p.Pro87Pro	synonymous	Exon 3 of 14	ENSP00000339883.2
	LBR	ENST00000425080.1	TSL:3	c.261T>G	p.Pro87Pro	synonymous	Exon 3 of 5	ENSP00000388059.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151974 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 56

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151974 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74204

African (AFR) AF: 0.00 AC: 0 AN: 41336

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 14721

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.79
Mutation Taster		=100/0	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: rs1056608; hg19: chr1-225609884;