2-140239515-C-A

Variant names:

• chr2-140239515-C-A
• rs1238324748
• NM_018557.3:c.13342G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018557.3(LRP1B):​c.13342G>T​(p.Val4448Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

Genes affected

LRP1B (HGNC:6693): (LDL receptor related protein 1B) This gene encodes a member of the low density lipoprotein (LDL) receptor family. These receptors play a wide variety of roles in normal cell function and development due to their interactions with multiple ligands. Disruption of this gene has been reported in several types of cancer. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1B	NM_018557.3	c.13342G>T	p.Val4448Leu	missense_variant	Exon 88 of 91	ENST00000389484.8	NP_061027.2
LRP1B	XM_017004341.2	c.12952G>T	p.Val4318Leu	missense_variant	Exon 88 of 91		XP_016859830.1
LRP1B	XM_017004342.1	c.8194G>T	p.Val2732Leu	missense_variant	Exon 59 of 62		XP_016859831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1B	ENST00000389484.8	c.13342G>T	p.Val4448Leu	missense_variant	Exon 88 of 91	1	NM_018557.3	ENSP00000374135.3
LRP1B	ENST00000437977.5	c.2035G>T	p.Val679Leu	missense_variant	Exon 15 of 17	5		ENSP00000415052.1
LRP1B	ENST00000442974.1	c.649G>T	p.Val217Leu	missense_variant	Exon 6 of 7	5		ENSP00000393859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450906 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13342G>T (p.V4448L) alteration is located in exon 88 (coding exon 88) of the LRP1B gene. This alteration results from a G to T substitution at nucleotide position 13342, causing the valine (V) at amino acid position 4448 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.094	T
Eigen	Benign	0.093
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.19
Sift	Benign	0.043	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.39	B
Vest4		0.89
MutPred		0.41		Loss of sheet (P = 0.0011);
MVP		0.12
MPC		0.22
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1238324748; hg19: chr2-140997084;