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GeneBe

1-216084723-A-G

Variant summary

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

The NM_206933.4(USH2A):c.5142T>C(p.Asn1714=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 1,613,344 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 8 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.14
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]
USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-216084723-A-G is Benign according to our data. Variant chr1-216084723-A-G is described in ClinVar as [Benign]. Clinvar id is 48529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216084723-A-G is described in Lovd as [Benign]. Variant chr1-216084723-A-G is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-4.14 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000874 (133/152238) while in subpopulation EAS AF= 0.0199 (103/5166). AF 95% confidence interval is 0.0168. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.5142T>C p.Asn1714= synonymous_variant 25/72 ENST00000307340.8
USH2A-AS2NR_125992.1 linkuse as main transcriptn.266-1999A>G intron_variant, non_coding_transcript_variant
USH2A-AS2NR_125993.1 linkuse as main transcriptn.137-1999A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.5142T>C p.Asn1714= synonymous_variant 25/721 NM_206933.4 P1O75445-1
USH2A-AS2ENST00000446411.5 linkuse as main transcriptn.266-1999A>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000881
AC:
134
AN:
152120
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0201
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00164
AC:
411
AN:
250536
Hom.:
3
AF XY:
0.00150
AC XY:
203
AN XY:
135378
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0200
Gnomad SAS exome
AF:
0.00105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000820
GnomAD4 exome
AF:
0.000610
AC:
891
AN:
1461106
Hom.:
8
Cov.:
30
AF XY:
0.000625
AC XY:
454
AN XY:
726866
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000896
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0168
Gnomad4 SAS exome
AF:
0.000870
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00215
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000874
AC:
133
AN:
152238
Hom.:
1
Cov.:
32
AF XY:
0.000833
AC XY:
62
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0199
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000740
Asia WGS
AF:
0.0140
AC:
49
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 26, 2015p.Asn1714Asn in exon 25 of USH2A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence and has been reported in 1.9% (162/8634) of Ea st Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs143546878). -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 25, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxAug 13, 2018This variant is associated with the following publications: (PMID: 19737284, 22135276) -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Usher syndrome type 2A Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 07, 2019- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinitis pigmentosa 39 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinal dystrophy Benign:1
Benign, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
Cadd
Benign
0.52
Dann
Benign
0.63

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: rs143546878; hg19: chr1-216258065; COSMIC: COSV56336674; API