2-140274491-C-T

Position:

• chr2-140274491-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018557.3(LRP1B):​c.13075G>A​(p.Asp4359Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.13075G>A	p.Asp4359Asn	missense_variant	85/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.12685G>A	p.Asp4229Asn	missense_variant	85/91
LRP1B	XM_017004342.1	c.7927G>A	p.Asp2643Asn	missense_variant	56/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.13075G>A	p.Asp4359Asn	missense_variant	85/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1771G>A	p.Asp591Asn	missense_variant	12/17	5
LRP1B	ENST00000442974.1	c.271G>A	p.Asp91Asn	missense_variant	2/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.13075G>A (p.D4359N) alteration is located in exon 85 (coding exon 85) of the LRP1B gene. This alteration results from a G to A substitution at nucleotide position 13075, causing the aspartic acid (D) at amino acid position 4359 to be replaced by an asparagine (N). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Benign	0.53	T
Sift4G	Benign	0.47	T
Polyphen		0.99	D
Vest4		0.78
MutPred		0.43		Loss of ubiquitination at K4360 (P = 0.0736);
MVP		0.54
MPC		0.43
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-141032060;