rs375918278

chr19-2434993-G-Achr19-2434993-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_032737.4(LMNB2):c.855+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,234,354 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (9 hom.)
• Consequence: LMNB2 NM_032737.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005497
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.499

Genes affected

LMNB2 (HGNC:6638): (lamin B2) This gene encodes a B type nuclear lamin. The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Mutations in this gene are associated with acquired partial lipodystrophy. [provided by RefSeq, May 2012]

MIR7108 (HGNC:49998): (microRNA 7108) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-2434993-G-A is Benign according to our data. Variant chr19-2434993-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNB2	NM_032737.4	c.855+8C>T		splice_region_variant, intron_variant		ENST00000325327.4
MIR7108	NR_106958.1	n.8C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNB2	ENST00000325327.4	c.855+8C>T		splice_region_variant, intron_variant		1	NM_032737.4	P1
MIR7108	ENST00000614319.1	n.8C>T		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 52 AN: 143742 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000960

Gnomad ASJ AF: 0.00419

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00233

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000122

Gnomad OTH AF: 0.000978

GnomAD3 exomes AF: 0.000553 AC: 128 AN: 231436 Hom.: 1 AF XY: 0.000665 AC XY: 85 AN XY: 127852

Gnomad AFR exome AF: 0.0000686

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000416 AC: 454 AN: 1090472 Hom.: 9 Cov.: 46 AF XY: 0.000540 AC XY: 295 AN XY: 546236

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.000546

Gnomad4 ASJ exome AF: 0.00403

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000785

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.000361 AC: 52 AN: 143882 Hom.: 0 Cov.: 33 AF XY: 0.000385 AC XY: 27 AN XY: 70144

Gnomad4 AFR AF: 0.000124

Gnomad4 AMR AF: 0.000958

Gnomad4 ASJ AF: 0.00419

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00232

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000122

Gnomad4 OTH AF: 0.000968

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lipodystrophy, partial, acquired, susceptibility to;C4225289:Progressive myoclonic epilepsy type 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

LMNB2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	9.5
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.022
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: rs375918278; hg19: chr19-2434991;