Genetic Variant LMNB1:n.-583G>C (chr5-126776926-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000460265.5(LMNB1):n.-583G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 152,314 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMNB1
ENST00000460265.5 non_coding_transcript_exon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0790

Publications

0 publications found

Variant links:

Genes affected

LMNB1 (HGNC:6637): (lamin B1) This gene encodes one of the two B-type lamin proteins and is a component of the nuclear lamina. A duplication of this gene is associated with autosomal dominant adult-onset leukodystrophy (ADLD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

LMNB1 Gene-Disease associations (from GenCC):

microcephaly 26, primary, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
adult-onset autosomal dominant demyelinating leukodystrophy
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
microcephaly
Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
autosomal dominant primary microcephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LMNB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 5-126776926-G-C is Benign according to our data. Variant chr5-126776926-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 350601.

BS2

High AC in GnomAd4 at 63 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000460265.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LMNB1	NR_134488.1		n.304G>C	non_coding_transcript_exon	Exon 1 of 12
LMNB1	NM_005573.4	MANE Select	c.-583G>C	upstream_gene	N/A	NP_005564.1	P20700
LMNB1	NM_001198557.2		c.-590G>C	upstream_gene	N/A	NP_001185486.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LMNB1	ENST00000460265.5	TSL:1	n.-583G>C	non_coding_transcript_exon	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5
LMNB1	ENST00000460265.5	TSL:1	n.-583G>C	5_prime_UTR	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5
LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.-583G>C	upstream_gene	N/A	ENSP00000261366.5	P20700

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00191

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

216

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

230

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.000414

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41584

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000484

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukodystrophy, Adult-Onset (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

-0.079

PromoterAI

-0.088

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over