chr5-126777524-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005573.4(LMNB1):​c.16C>G​(p.Pro6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000081 in 1,234,760 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: LMNB1 NM_005573.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28922397).

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>G	p.Pro6Ala	missense	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.-272+280C>G		intron	N/A	NP_001185486.1
	LMNB1	NR_134488.1		n.902C>G		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>G	p.Pro6Ala	missense	Exon 1 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000395354.1	TSL:1	c.16C>G	p.Pro6Ala	missense	Exon 1 of 6	ENSP00000378761.1	E9PBF6
	LMNB1	ENST00000460265.5	TSL:1	n.16C>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1234760 Hom.: 0 Cov.: 30 AF XY: 0.00000166 AC XY: 1 AN XY: 601894

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

American (AMR) AF: 0.00 AC: 0 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: 9.98e-7 AC: 1 AN: 1001780

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.58
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.37
Sift	Benign	0.049	D
Sift4G	Benign	0.075	T
Polyphen		0.30	B
Vest4		0.38
MutPred		0.23		Gain of MoRF binding (P = 0.0191)
MVP		0.67
MPC		0.40
ClinPred		0.27	T
GERP RS		2.7
PromoterAI		0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.15
gMVP		0.22
Mutation Taster		=68/32	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;