rs373757

Variant names:

• chr2-141254732-T-C
• rs373757
• NM_018557.3:c.344-91A>G

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_018557.3(LRP1B):c.344-91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.223 (AC=217,127) in the gnomAD database across 972,638 control chromosomes, including 24,812 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.259. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3532 hom., cov: 32)
  • Exomes 𝑓: 0.23 (21280 hom.)
• Consequence: LRP1B NM_018557.3 intron
• Predictors: AlphaGenome AVI: 2: Benign
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 6 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2591 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_018557.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LRP1B NM_018557.3	MANE Select	c.344-91A>G	intron	Intron 3 of 90	Prot: NP_061027.2 UniProt:

LRP1B NM_018557.3

MANE Select

HGVSc / HGVSpc.344-91A>G

Exon rankIntron 3 of 90

intron

Prot: NP_061027.2UniProt: Q9NZR2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LRP1B ENST00000389484.8	TSL:1MANE Select	c.344-91A>G	intron	Intron 3 of 90	Prot: ENSP00000374135.3 UniProt:
	LRP1B ENST00000434794.1	TSL:2	c.206-272456A>G	intron	Intron 2 of 13	Prot: ENSP00000413239.1 UniProt:

LRP1B ENST00000389484.8

TSL:1MANE Select

HGVSc / HGVSpc.344-91A>G

Exon rankIntron 3 of 90

intron

Prot: ENSP00000374135.3UniProt: Q9NZR2

LRP1B ENST00000434794.1

TSL:2

HGVSc / HGVSpc.206-272456A>G

Exon rankIntron 2 of 13

intron

Prot: ENSP00000413239.1UniProt: E7ERG8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.213	AC:32289	Hom:3520	AN:151892	Cov:32
GnomAD4 exome	AF: 0.225	AC:184800	Hom:21280	AN:820628	Cov:
GnomAD4 genome	AF: 0.213	AC:32327	Hom:3532	AN:152010	Cov:32
TOPMed (Bravo)	AF: 0.213	AC:56379	Hom:6088	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.217	AC:19617	Hom:2104	AN:90370	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.196	AC:459	Hom:46	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.209	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.221	AC:66	Hom:	AN:298	Cov:
GenomeAsia100K	AF: 0.219	AC:761	Hom:	AN:3470	Cov:
Korea4K (4,157 Koreans)	AF: 0.169	AC:1219	Hom:	AN:7222	Cov:
Qatari Genome	AF: 0.176	AC:31	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.132	AC:16047	Hom:1076	AN:121640	Cov:
Turkish Variome	AF: 0.220	AC:340	Hom:37	AN:1546	Cov:
UK10K	AF: 0.225	AC:1703	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.196	AC:1758	Hom:180	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.138	6706	48550	0.143	12795	89400

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.6
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.63
GPN-Star LLR	N/A	-0.034
GPN-Star score	N/A	0.034
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.27

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373757;

hg19: chr2-142012301;

COSMIC: COSV104431431;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar