rs193921022

Positions:

• chr2-140700401-C-A
• chr2-140700401-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018557.3(LRP1B):​c.6648G>T​(p.Glu2216Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.121

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRP1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.17271784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.6648G>T	p.Glu2216Asp	missense_variant	41/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.6258G>T	p.Glu2086Asp	missense_variant	41/91
LRP1B	XM_047444771.1	c.6759G>T	p.Glu2253Asp	missense_variant	41/77
LRP1B	XM_017004342.1	c.1500G>T	p.Glu500Asp	missense_variant	12/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.6648G>T	p.Glu2216Asp	missense_variant	41/91	1	NM_018557.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.68	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.083	B
Vest4		0.43
MutPred		0.20		Loss of loop (P = 0.1242);
MVP		0.51
MPC		0.25
ClinPred		0.76	D
GERP RS		1.5
Varity_R		0.22
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs193921022; hg19: chr2-141457970; COSMIC: COSV67269595;