NM_005573.4:c.16C>T

Variant names:

• chr5-126777524-C-T
• rs758245272
• NM_005573.4:c.16C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_005573.4(LMNB1):​c.16C>T​(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000243 in 1,234,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: LMNB1 NM_005573.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.583
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22132519).
• BP6: Variant 5-126777524-C-T is Benign according to our data. Variant chr5-126777524-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2234603.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005573.4. 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
	LMNB1	NM_005573.4	MANE Select	c.16C>T	p.Pro6Ser	missense	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.-272+280C>T		intron	N/A	NP_001185486.1
	LMNB1	NR_134488.1		n.902C>T		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.16C>T	p.Pro6Ser	missense	Exon 1 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000395354.1	TSL:1	c.16C>T	p.Pro6Ser	missense	Exon 1 of 6	ENSP00000378761.1	E9PBF6
	LMNB1	ENST00000460265.5	TSL:1	n.16C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000530 AC: 2 AN: 37718 AF XY: 0.0000911

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000243 AC: 3 AN: 1234760 Hom.: 0 Cov.: 30 AF XY: 0.00000498 AC XY: 3 AN XY: 601894

African (AFR) AF: 0.00 AC: 0 AN: 24624

American (AMR) AF: 0.000221 AC: 3 AN: 13596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18206

East Asian (EAS) AF: 0.00 AC: 0 AN: 27440

South Asian (SAS) AF: 0.00 AC: 0 AN: 53220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1001780

Other (OTH) AF: 0.00 AC: 0 AN: 50324

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000255 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.58
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		0.30	B
Vest4		0.43
MutPred		0.20		Gain of MoRF binding (P = 0.0075)
MVP		0.63
MPC		0.51
ClinPred		0.11	T
GERP RS		2.7
PromoterAI		0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.17
gMVP		0.27
Mutation Taster		=71/29	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: rs758245272; hg19: chr5-126113216;