2-43805247-G-A
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The ENST00000378587.3(DYNC2LI1):c.943G>A(p.Val315Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000221 in 1,587,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V315V) has been classified as Pathogenic.
Frequency
Consequence
ENST00000378587.3 missense
Scores
Clinical Significance
Conservation
Publications
- short-rib thoracic dysplasia 15 with polydactylyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- Ellis-van Creveld syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Jeune syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2LI1 | NM_016008.4 | c.993+1G>A | splice_donor_variant, intron_variant | Intron 12 of 12 | ENST00000260605.12 | NP_057092.2 | ||
DYNC2LI1 | NM_001348913.2 | c.996+1G>A | splice_donor_variant, intron_variant | Intron 12 of 13 | NP_001335842.1 | |||
DYNC2LI1 | NM_001348912.2 | c.993+1G>A | splice_donor_variant, intron_variant | Intron 12 of 13 | NP_001335841.1 | |||
DYNC2LI1 | NM_001193464.2 | c.996+1G>A | splice_donor_variant, intron_variant | Intron 12 of 12 | NP_001180393.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2LI1 | ENST00000378587.3 | c.943G>A | p.Val315Ile | missense_variant | Exon 11 of 11 | 1 | ENSP00000367850.3 | |||
DYNC2LI1 | ENST00000260605.12 | c.993+1G>A | splice_donor_variant, intron_variant | Intron 12 of 12 | 1 | NM_016008.4 | ENSP00000260605.8 | |||
DYNC2LI1 | ENST00000605786.5 | c.996+1G>A | splice_donor_variant, intron_variant | Intron 12 of 12 | 1 | ENSP00000474032.1 | ||||
DYNC2LI1 | ENST00000482738.1 | n.*70G>A | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000201 AC: 5AN: 248506 AF XY: 0.0000223 show subpopulations
GnomAD4 exome AF: 0.0000237 AC: 34AN: 1434956Hom.: 0 Cov.: 24 AF XY: 0.0000182 AC XY: 13AN XY: 715496 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306 show subpopulations
ClinVar
Submissions by phenotype
Asphyxiating thoracic dystrophy 1 Pathogenic:1
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not provided Pathogenic:1
This sequence change affects a donor splice site in intron 12 of the DYNC2LI1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs374356079, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with short rib polydactyly syndrome (PMID: 26077881). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212764). Studies have shown that disruption of this splice site alters DYNC2LI1 gene expression (PMID: 26077881). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 26077881). For these reasons, this variant has been classified as Pathogenic. -
Short-rib thoracic dysplasia 15 with polydactyly Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at