rs56222536

chr1-216084871-A-Gchr1-216084871-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):c.4994T>C(p.Ile1665Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,682 control chromosomes in the GnomAD database, including 14,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1044 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13535 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.681

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)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014926493).
• BP6: Variant 1-216084871-A-G is Benign according to our data. Variant chr1-216084871-A-G is described in ClinVar as [Benign]. Clinvar id is 48525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216084871-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.4994T>C	p.Ile1665Thr	missense_variant	25/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.266-1851A>G		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.137-1851A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.4994T>C	p.Ile1665Thr	missense_variant	25/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.266-1851A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15330 AN: 152112 Hom.: 1044 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.0705

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.110 AC: 27645 AN: 250302 Hom.: 1891 AF XY: 0.113 AC XY: 15271 AN XY: 135380

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.0209

Gnomad SAS exome AF: 0.0744

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 191566 AN: 1460452 Hom.: 13535 Cov.: 32 AF XY: 0.130 AC XY: 94740 AN XY: 726616

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.0891

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.0213

Gnomad4 SAS exome AF: 0.0744

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.101 AC: 15331 AN: 152230 Hom.: 1044 Cov.: 32 AF XY: 0.101 AC XY: 7482 AN XY: 74420

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.0710

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.129

Alfa AF: 0.136 Hom.: 2168

Bravo AF: 0.0974

TwinsUK AF: 0.136 AC: 504

ALSPAC AF: 0.144 AC: 554

ESP6500AA AF: 0.0282 AC: 124

ESP6500EA AF: 0.157 AC: 1354

ExAC AF: 0.110 AC: 13301

Asia WGS AF: 0.0610 AC: 212 AN: 3476

EpiCase AF: 0.153

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2013	This 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 submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	8.1
Dann	Benign	0.92
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Uncertain	0.041	D
Polyphen		0.0070	B
Vest4		0.075
MPC		0.035
ClinPred		0.0013	T
GERP RS		2.6
Varity_R		0.089
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs56222536; hg19: chr1-216258213; COSMIC: COSV56370415;