chr2-169257123-C-T
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_004525.3(LRP2):c.2639+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004525.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- Donnai-Barrow syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
- Stickler syndromeInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- intellectual disabilityInheritance: AD Classification: LIMITED Submitted by: G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.2639+1G>A | splice_donor_variant, intron_variant | Intron 18 of 78 | ENST00000649046.1 | NP_004516.2 | ||
LRP2 | XM_011511183.4 | c.2639+1G>A | splice_donor_variant, intron_variant | Intron 18 of 77 | XP_011509485.1 | |||
LRP2 | XM_047444340.1 | c.1715+1G>A | splice_donor_variant, intron_variant | Intron 18 of 78 | XP_047300296.1 | |||
LRP2 | XM_011511184.3 | c.350+1G>A | splice_donor_variant, intron_variant | Intron 3 of 63 | XP_011509486.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.2639+1G>A | splice_donor_variant, intron_variant | Intron 18 of 78 | NM_004525.3 | ENSP00000496870.1 | ||||
LRP2 | ENST00000443831.1 | c.2228+1G>A | splice_donor_variant, intron_variant | Intron 16 of 22 | 2 | ENSP00000409813.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250828 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460262Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726466 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274 show subpopulations
ClinVar
Submissions by phenotype
Donnai-Barrow syndrome Pathogenic:4
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ACMG classification criteria: PVS1 moderate, PM2 supporting, PM3 moderate, PP1 supporting -
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not provided Pathogenic:1
This sequence change affects a donor splice site in intron 18 of the LRP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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. Disruption of this splice site has been observed in individuals with Donnai-Barrow syndrome (PMID: 23048173; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 559644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at