Genetic Variant NM_013437.5:c.2482C>A (chr8-104490771-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013437.5(LRP12):c.2482C>A(p.Arg828Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R828C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRP12
NM_013437.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.14

Publications

0 publications found

Variant links:

Genes affected

LRP12 (HGNC:31708): (LDL receptor related protein 12) This gene encodes a member of the low-density lipoprotein receptor related protein family. The product of this gene is a transmembrane protein that is differentially expressed in many cancer cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

LRP12 Gene-Disease associations (from GenCC):

oculopharyngodistal myopathy 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

LRP12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.097443104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP12	NM_013437.5 link	c.2482C>A	p.Arg828Ser	missense_variant	Exon 7 of 7	ENST00000276654.10	NP_038465.1	Q9Y561-1Q59H02
LRP12	NM_001135703.3 link	c.2425C>A	p.Arg809Ser	missense_variant	Exon 6 of 6		NP_001129175.1	Q9Y561-2Q59H02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP12	ENST00000276654.10 link	c.2482C>A	p.Arg828Ser	missense_variant	Exon 7 of 7	1	NM_013437.5	ENSP00000276654.5	Q9Y561-1
LRP12	ENST00000424843.6 link	c.2425C>A	p.Arg809Ser	missense_variant	Exon 6 of 6	2		ENSP00000399148.2	Q9Y561-2
LRP12	ENST00000518375.1 link	n.1835C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.00052

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.097

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.20

.;N

PhyloP100

5.1

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.21

Sift

Benign

0.17

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0010

B;B

Vest4

0.18

MutPred

0.22

.;Gain of disorder (P = 0.1464);

MVP

0.41

MPC

0.27

ClinPred

0.54

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.17

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over