2-169246841-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.3054C>A(p.Thr1018Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,613,768 control chromosomes in the GnomAD database, including 178,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1018T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.42 ( 14430 hom., cov: 32)

Exomes 𝑓: 0.47 ( 164253 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.335

Publications

26 publications found

Variant links:

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

LRP2 Gene-Disease associations (from GenCC):

Donnai-Barrow syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Stickler syndrome
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P
congenital heart disease
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-169246841-G-T is Benign according to our data. Variant chr2-169246841-G-T is described in ClinVar as Benign. ClinVar VariationId is 129515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.335 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.3054C>A	p.Thr1018Thr	synonymous	Exon 21 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.3054C>A	p.Thr1018Thr	synonymous	Exon 21 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.2643C>A	p.Thr881Thr	synonymous	Exon 19 of 23	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes

AF:

0.424

AC:

64440

AN:

151844

Hom.:

14409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.452

Gnomad AMR

AF:

0.523

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.472

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.417

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.461

Gnomad OTH

AF:

0.443

GnomAD2 exomes

AF:

0.501

AC:

125852

AN:

251406

AF XY:

0.507

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.641

Gnomad ASJ exome

AF:

0.560

Gnomad EAS exome

AF:

0.472

Gnomad FIN exome

AF:

0.423

Gnomad NFE exome

AF:

0.460

Gnomad OTH exome

AF:

0.470

GnomAD4 exome

AF:

0.468

AC:

684595

AN:

1461806

Hom.:

164253

Cov.:

AF XY:

0.475

AC XY:

345336

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.270

AC:

9055

AN:

33478

American (AMR)

AF:

0.627

AC:

28049

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.557

AC:

14546

AN:

26134

East Asian (EAS)

AF:

0.454

AC:

18032

AN:

39700

South Asian (SAS)

AF:

0.663

AC:

57220

AN:

86252

European-Finnish (FIN)

AF:

0.420

AC:

22446

AN:

53418

Middle Eastern (MID)

AF:

0.478

AC:

2757

AN:

5768

European-Non Finnish (NFE)

AF:

0.453

AC:

504160

AN:

1111938

Other (OTH)

AF:

0.469

AC:

28330

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

21239

42478

63717

84956

106195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15208

30416

45624

60832

76040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.424

AC:

64498

AN:

151962

Hom.:

14430

Cov.:

AF XY:

0.428

AC XY:

31760

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.281

AC:

11663

AN:

41448

American (AMR)

AF:

0.524

AC:

7986

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.565

AC:

1959

AN:

3466

East Asian (EAS)

AF:

0.472

AC:

2431

AN:

5152

South Asian (SAS)

AF:

0.673

AC:

3237

AN:

4812

European-Finnish (FIN)

AF:

0.417

AC:

4406

AN:

10568

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.461

AC:

31308

AN:

67946

Other (OTH)

AF:

0.449

AC:

948

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1854

3708

5563

7417

9271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.422

Hom.:

7529

Bravo

AF:

0.423

Asia WGS

AF:

0.582

AC:

2022

AN:

3478

EpiCase

AF:

0.465

EpiControl

AF:

0.460

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.49

(source)

DANN

Benign

0.29

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over