1-215934756-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):​c.7160T>C​(p.Met2387Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000731 in 1,612,662 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

3
15

Clinical Significance

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

Conservation

PhyloP100: 5.14
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.023505151).
BP6
Variant 1-215934756-A-G is Benign according to our data. Variant chr1-215934756-A-G is described in ClinVar as [Benign]. Clinvar id is 48578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215934756-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00403 (613/152118) while in subpopulation AFR AF= 0.0142 (589/41546). AF 95% confidence interval is 0.0132. There are 6 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.7160T>C p.Met2387Thr missense_variant Exon 38 of 72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.7160T>C p.Met2387Thr missense_variant Exon 38 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.7160T>C p.Met2387Thr missense_variant Exon 38 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00402
AC:
611
AN:
152000
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0142
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000921
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.000973
AC:
244
AN:
250850
Hom.:
1
AF XY:
0.000590
AC XY:
80
AN XY:
135554
show subpopulations
Gnomad AFR exome
AF:
0.0137
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.000655
GnomAD4 exome
AF:
0.000388
AC:
566
AN:
1460544
Hom.:
0
Cov.:
31
AF XY:
0.000325
AC XY:
236
AN XY:
726562
show subpopulations
Gnomad4 AFR exome
AF:
0.0144
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.000531
GnomAD4 genome
AF:
0.00403
AC:
613
AN:
152118
Hom.:
6
Cov.:
32
AF XY:
0.00370
AC XY:
275
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0142
Gnomad4 AMR
AF:
0.000920
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.000663
Hom.:
1
Bravo
AF:
0.00450
ESP6500AA
AF:
0.0132
AC:
58
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00127
AC:
154

ClinVar

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

Submissions by phenotype

not specified Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Met2387Thr in exon 38 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (50/3738) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http: //evs.gs.washington.edu/EVS/; dbSNP rs115015305). -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A Benign:2
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa 39 Benign:1
Nov 04, 2023
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
15
DANN
Benign
0.83
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.44
T
MetaRNN
Benign
0.024
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.099
Sift
Uncertain
0.019
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.45
P
Vest4
0.48
MVP
0.60
MPC
0.041
ClinPred
0.035
T
GERP RS
4.5
Varity_R
0.24
gMVP
0.40

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: rs115015305; hg19: chr1-216108098; API