rs12073994

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000307340.8(USH2A):​c.10851C>T​(p.Asn3617=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,028 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 8 hom. )

Consequence

USH2A
ENST00000307340.8 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.222
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 1-215779931-G-A is Benign according to our data. Variant chr1-215779931-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.222 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (707/152154) while in subpopulation AFR AF= 0.0162 (672/41482). AF 95% confidence interval is 0.0152. There are 4 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.10851C>T p.Asn3617= synonymous_variant 55/72 ENST00000307340.8 NP_996816.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.10851C>T p.Asn3617= synonymous_variant 55/721 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000674083.1 linkuse as main transcriptc.10851C>T p.Asn3617= synonymous_variant 55/73 ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00464
AC:
706
AN:
152036
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0162
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00138
AC:
346
AN:
251406
Hom.:
2
AF XY:
0.000979
AC XY:
133
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.0172
Gnomad AMR exome
AF:
0.00110
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000646
AC:
945
AN:
1461874
Hom.:
8
Cov.:
32
AF XY:
0.000583
AC XY:
424
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0159
Gnomad4 AMR exome
AF:
0.00101
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000232
Gnomad4 OTH exome
AF:
0.00152
GnomAD4 genome
AF:
0.00465
AC:
707
AN:
152154
Hom.:
4
Cov.:
32
AF XY:
0.00429
AC XY:
319
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.0162
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00236
Hom.:
0
Bravo
AF:
0.00523
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 07, 2012Asn3617Asn in Exon 55 of USH2A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.7% (62/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs12073994). -
Benign, criteria provided, single submitterclinical testingGeneDxApr 04, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 19, 2021- -
Retinitis pigmentosa 39 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Usher syndrome type 2A Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
0.31
DANN
Benign
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs12073994; hg19: chr1-215953273; API