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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0890
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkc.4252-16_4252-13dupCTTT intron_variant ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.4252-16_4252-13dupCTTT intron_variant NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.4252-13_4252-12insCTTT intron_variant 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.4252-13_4252-12insCTTT intron_variant 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.4252-13_4252-12insCTTT intron_variant ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.000659
AC:
100
AN:
151652
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000703
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000593
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00213
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000486
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000596
AC:
146
AN:
244842
Hom.:
0
AF XY:
0.000521
AC XY:
69
AN XY:
132502
show subpopulations
Gnomad AFR exome
AF:
0.000946
Gnomad AMR exome
AF:
0.000740
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00172
Gnomad SAS exome
AF:
0.000398
Gnomad FIN exome
AF:
0.000402
Gnomad NFE exome
AF:
0.000467
Gnomad OTH exome
AF:
0.000502
GnomAD4 exome
AF:
0.000515
AC:
750
AN:
1457366
Hom.:
0
Cov.:
32
AF XY:
0.000501
AC XY:
363
AN XY:
725138
show subpopulations
Gnomad4 AFR exome
AF:
0.00123
Gnomad4 AMR exome
AF:
0.000696
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.000961
Gnomad4 SAS exome
AF:
0.000465
Gnomad4 FIN exome
AF:
0.000535
Gnomad4 NFE exome
AF:
0.000480
Gnomad4 OTH exome
AF:
0.000599
GnomAD4 genome
AF:
0.000659
AC:
100
AN:
151768
Hom.:
0
Cov.:
31
AF XY:
0.000701
AC XY:
52
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.000701
Gnomad4 AMR
AF:
0.000592
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00213
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.000486
Gnomad4 OTH
AF:
0.000948

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 submitterclinical testingGeneDxMay 09, 2022See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 23, 2024- -
Retinitis Pigmentosa, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Retinitis pigmentosa-deafness syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 10, 2024Variant 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372388546; hg19: chr1-216363721; API