rs727503723
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_206933.4(USH2A):βc.6795_6797delβ(p.Glu2265_Tyr2266delinsAsp) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000149 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 32)
Exomes π: 0.000014 ( 0 hom. )
Consequence
USH2A
NM_206933.4 inframe_deletion
NM_206933.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.65
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 Pathogenic. Variant got 13 ACMG points.
PM1
?
In a domain Fibronectin type-III 9 (size 87) in uniprot entity USH2A_HUMAN there are 41 pathogenic changes around while only 8 benign (84%) in NM_206933.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_206933.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 1-215993027-ATAT-A is Pathogenic according to our data. Variant chr1-215993027-ATAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 166478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215993027-ATAT-A is described in Lovd as [Pathogenic]. Variant chr1-215993027-ATAT-A is described in Lovd as [Pathogenic]. Variant chr1-215993027-ATAT-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.6795_6797del | p.Glu2265_Tyr2266delinsAsp | inframe_deletion | 35/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.6795_6797del | p.Glu2265_Tyr2266delinsAsp | inframe_deletion | 35/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.6795_6797del | p.Glu2265_Tyr2266delinsAsp | inframe_deletion | 35/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251138Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135710
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461794Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727200
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This variant, c.6795_6797del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the USH2A protein (p.Glu2265_Tyr2266delinsAsp). This variant is present in population databases (rs727503723, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22135276, 26667666, 27957503). 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: 166478). For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 18, 2017 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Usher syndrome type 2A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 09, 2018 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at