NM_032737.4:c.855+8C>T

Variant names:

• chr19-2434993-G-A
• rs375918278
• NM_032737.4:c.855+8C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.499
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -16 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 Benign/Likely_benign. ClinVar VariationId is 542444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032737.4. 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
	LMNB2	NM_032737.4	MANE Select	c.855+8C>T		splice_region intron	N/A	NP_116126.3
	MIR7108	NR_106958.1		n.8C>T		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB2	ENST00000325327.4	TSL:1 MANE Select	c.855+8C>T		splice_region intron	N/A	ENSP00000327054.3	Q03252
	LMNB2	ENST00000917224.1		c.996+8C>T		splice_region intron	N/A	ENSP00000587283.1
	LMNB2	ENST00000917223.1		c.855+8C>T		splice_region intron	N/A	ENSP00000587282.1

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

GnomAD2 exomes AF: 0.000553 AC: 128 AN: 231436 AF XY: 0.000665

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 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

African (AFR) AF: 0.00118 AC: 29 AN: 24632

American (AMR) AF: 0.000546 AC: 21 AN: 38440

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 67 AN: 16642

East Asian (EAS) AF: 0.00 AC: 0 AN: 18184

South Asian (SAS) AF: 0.00229 AC: 186 AN: 81052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26294

Middle Eastern (MID) AF: 0.00577 AC: 24 AN: 4158

European-Non Finnish (NFE) AF: 0.0000785 AC: 66 AN: 840294

Other (OTH) AF: 0.00150 AC: 61 AN: 40776

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

African (AFR) AF: 0.000124 AC: 5 AN: 40192

American (AMR) AF: 0.000958 AC: 14 AN: 14618

Ashkenazi Jewish (ASJ) AF: 0.00419 AC: 14 AN: 3338

East Asian (EAS) AF: 0.00 AC: 0 AN: 4118

South Asian (SAS) AF: 0.00232 AC: 9 AN: 3884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000122 AC: 8 AN: 65388

Other (OTH) AF: 0.000968 AC: 2 AN: 2066

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lipodystrophy, partial, acquired, susceptibility to;C4225289:Progressive myoclonic epilepsy type 9 (1)
-	-	1	LMNB2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.5
DANN	Benign	0.89
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs375918278; hg19: chr19-2434991;