2-169140514-TG-TGG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004525.3(LRP2):βc.13139_13140insCβ(p.Cys4381MetfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000087 in 1,586,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P4380P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004525.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.13139_13140insC | p.Cys4381MetfsTer12 | frameshift_variant | 72/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.13010_13011insC | p.Cys4338MetfsTer12 | frameshift_variant | 71/78 | ||
LRP2 | XM_011511184.3 | c.10850_10851insC | p.Cys3618MetfsTer12 | frameshift_variant | 57/64 | ||
LRP2 | XM_047444340.1 | c.12215_12216insC | p.Cys4073MetfsTer12 | frameshift_variant | 72/79 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.13139_13140insC | p.Cys4381MetfsTer12 | frameshift_variant | 72/79 | NM_004525.3 | P1 | ||
LRP2 | ENST00000649153.1 | c.4009-905_4009-904insC | intron_variant, NMD_transcript_variant | ||||||
LRP2 | ENST00000650252.1 | c.*820-7_*820-6insC | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000593 AC: 9AN: 151704Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000899 AC: 129AN: 1434940Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 61AN XY: 714760
GnomAD4 genome AF: 0.0000593 AC: 9AN: 151822Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 5AN XY: 74210
ClinVar
Submissions by phenotype
Donnai-Barrow syndrome Pathogenic:2Other:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 26, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 12, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Cys4381Metfs*12) in the LRP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRP2 are known to be pathogenic (PMID: 17632512, 25682901). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Donnai-Barrow syndrome (PMID: 17632512). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21419). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | LRP2: PVS1, PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at