1-216190379-AAAAGAAAGAAAG-AAAAGAAAGAAAGAAAG
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_206933.4(USH2A):c.4252-16_4252-13dupCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,609,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00051 ( 0 hom. )
Consequence
USH2A
NM_206933.4 intron
NM_206933.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0890
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 1-216190379-A-AAAAG is Benign according to our data. Variant chr1-216190379-A-AAAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295427.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.4252-13_4252-12insCTTT | intron_variant | 1 | NM_206933.4 | ENSP00000305941.3 | ||||
USH2A | ENST00000366942.3 | c.4252-13_4252-12insCTTT | intron_variant | 1 | ENSP00000355909.3 | |||||
USH2A | ENST00000674083.1 | c.4252-13_4252-12insCTTT | intron_variant | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.000659 AC: 100AN: 151652Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000596 AC: 146AN: 244842Hom.: 0 AF XY: 0.000521 AC XY: 69AN XY: 132502
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GnomAD4 exome AF: 0.000515 AC: 750AN: 1457366Hom.: 0 Cov.: 32 AF XY: 0.000501 AC XY: 363AN XY: 725138
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GnomAD4 genome AF: 0.000659 AC: 100AN: 151768Hom.: 0 Cov.: 31 AF XY: 0.000701 AC XY: 52AN XY: 74164
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2022 | See Variant Classification Assertion Criteria. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2024 | - - |
Retinitis Pigmentosa, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Retinitis pigmentosa-deafness syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2024 | Variant summary: USH2A c.4252-16_4252-13dupCTTT alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0006 in 244842 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0006 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4252-16_4252-13dupCTTT in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 295427). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at