rs41277194

chr1-215838066-T-C

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.9296A>G(p.Asn3099Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0302 in 1,613,804 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (145 hom., cov: 32)
  • Exomes 𝑓: 0.029 (738 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity USH2A_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027686954).
• BP6: Variant 1-215838066-T-C is Benign according to our data. Variant chr1-215838066-T-C is described in ClinVar as [Benign]. Clinvar id is 48620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838066-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9296A>G	p.Asn3099Ser	missense_variant	47/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9296A>G	p.Asn3099Ser	missense_variant	47/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9296A>G	p.Asn3099Ser	missense_variant	47/73

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 6013 AN: 152120 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0413

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0276 AC: 6943 AN: 251320 Hom.: 104 AF XY: 0.0269 AC XY: 3649 AN XY: 135812

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0292 AC: 42658 AN: 1461566 Hom.: 738 Cov.: 31 AF XY: 0.0286 AC XY: 20798 AN XY: 727088

Gnomad4 AFR exome AF: 0.0746

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0420

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0331

GnomAD4 genome AF: 0.0396 AC: 6028 AN: 152238 Hom.: 145 Cov.: 32 AF XY: 0.0392 AC XY: 2915 AN XY: 74452

Gnomad4 AFR AF: 0.0690

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.0413

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0313 Hom.: 145

Bravo AF: 0.0436

TwinsUK AF: 0.0256 AC: 95

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.0305 AC: 262

ExAC AF: 0.0283 AC: 3432

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0303

EpiControl AF: 0.0356

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2014	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.65	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.085
Sift	Benign	0.050	D
Sift4G	Uncertain	0.011	D
Polyphen		0.18	B
Vest4		0.13
MPC		0.033
ClinPred		0.021	T
GERP RS		2.6
Varity_R		0.089
gMVP		0.34

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

Other links and lift over

dbSNP: rs41277194; hg19: chr1-216011408; COSMIC: COSV56389703;