rs148000219

Positions:

• chr1-216175319-G-A
• chr1-216175319-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000307340.8(USH2A):​c.4560C>T​(p.Ile1520=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,613,778 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I1520I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: USH2A ENST00000307340.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: 0.0920

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-216175319-G-A is Benign according to our data. Variant chr1-216175319-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48518.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=3, Likely_benign=2}. Variant chr1-216175319-G-A is described in Lovd as [Likely_benign]. Variant chr1-216175319-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4560C>T	p.Ile1520=	synonymous_variant	21/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4560C>T	p.Ile1520=	synonymous_variant	21/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4560C>T	p.Ile1520=	synonymous_variant	21/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.4560C>T	p.Ile1520=	synonymous_variant	21/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.4560C>T	p.Ile1520=	synonymous_variant	21/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00250 AC: 626 AN: 250572 Hom.: 3 AF XY: 0.00249 AC XY: 337 AN XY: 135402

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000971

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00351 AC: 5129 AN: 1461518 Hom.: 11 Cov.: 32 AF XY: 0.00347 AC XY: 2521 AN XY: 727054

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00398

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74438

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00325 Hom.: 0

Bravo AF: 0.00220

EpiCase AF: 0.00333

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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	GeneDx	Mar 03, 2015	- -

Usher syndrome type 2A Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 31, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 30, 2014	Ile1520Ile in Exon 21A 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 0.3% (27/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs148000219). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.88
DANN	Benign	0.58

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: rs148000219; hg19: chr1-216348661; COSMIC: COSV56424773;