rs41315579
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 197/30616) of the p.Ser2445Phe variant in the USH2A gene is 0.57% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143592/MONDO:0019501/005
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.7334C>T | p.Ser2445Phe | missense_variant | 39/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.7334C>T | p.Ser2445Phe | missense_variant | 39/72 | 1 | NM_206933.4 | P1 | |
ENST00000414995.1 | n.208G>A | non_coding_transcript_exon_variant | 2/2 | 3 | |||||
USH2A | ENST00000674083.1 | c.7334C>T | p.Ser2445Phe | missense_variant | 39/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152144Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000841 AC: 211AN: 250880Hom.: 2 AF XY: 0.00111 AC XY: 150AN XY: 135548
GnomAD4 exome AF: 0.000357 AC: 522AN: 1461440Hom.: 3 Cov.: 31 AF XY: 0.000517 AC XY: 376AN XY: 727030
GnomAD4 genome ? AF: 0.000223 AC: 34AN: 152262Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74442
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The USH2A p.Ser2445Phe variant was identified in 1 of 1444 proband chromosomes (frequency: 0.00069) from individuals with inherited retinal disease (Carss_2017_PMID:28041643). The variant was identified in dbSNP (ID: rs41315579) and ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and Counsyl, and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 211 of 250880 chromosomes (2 homozygous) at a frequency of 0.000841 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 197 of 30616 chromosomes (freq: 0.006435), Other in 2 of 6114 chromosomes (freq: 0.000327), Latino in 3 of 34556 chromosomes (freq: 0.000087), European (non-Finnish) in 8 of 113262 chromosomes (freq: 0.000071) and East Asian in 1 of 18382 chromosomes (freq: 0.000054), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. Although the p.Ser2445 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | USH2A: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2019 | This variant is associated with the following publications: (PMID: 28041643) - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 09, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 14, 2011 | Variant classified as Uncertain Significance - Favor Pathogenic. The Ser2445Phe variant in USH2A has been previously reported in dbSNP (rs41315579) without freq uency information (one heterozygous submission). The Ser2445 residue is conserve d in several mammals and distant species up to Zebrafish but is replaced by alan ine in mouse and rat. Biochemical and computational analyses (PolyPhen, SIFT and AlignGVGD) suggest that the variant may impact the protein. In addition, the id entification of this variant in this patient with a likely pathogenic variant in USH2A and a phenotype consistent with Usher type 2, increases the likelihood th at this variant is disease-causing. In summary, the clinical significance of thi s variant cannot be determined with certainty at this time; however based upon t he arguments described above, we would lean towards a more likely pathogenic rol e. - |
Bardet-Biedl syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation | Jun 02, 2023 | - - |
Usher syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Mar 18, 2020 | The filtering allele frequency (the lower threshold of the 95% CI of 197/30616) of the p.Ser2445Phe variant in the USH2A gene is 0.57% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). - |
Usher syndrome type 2A Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 06, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at