1-216418661-T-C

Position:

• chr1-216418661-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.504A>G​(p.Thr168Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,612,398 control chromosomes in the GnomAD database, including 341,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29448 hom., cov: 31)
  • Exomes 𝑓: 0.65 (311915 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.565

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-216418661-T-C is Benign according to our data. Variant chr1-216418661-T-C is described in ClinVar as [Benign]. Clinvar id is 48528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216418661-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.565 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.504A>G	p.Thr168Thr	synonymous_variant	3/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.504A>G	p.Thr168Thr	synonymous_variant	3/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.504A>G	p.Thr168Thr	synonymous_variant	3/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.504A>G	p.Thr168Thr	synonymous_variant	3/21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.504A>G	p.Thr168Thr	synonymous_variant	3/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93643 AN: 151692 Hom.: 29431 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.610

GnomAD3 exomes AF: 0.653 AC: 163677 AN: 250764 Hom.: 54279 AF XY: 0.648 AC XY: 87863 AN XY: 135500

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.694

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.839

Gnomad SAS exome AF: 0.601

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.647

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.651 AC: 951291 AN: 1460588 Hom.: 311915 Cov.: 55 AF XY: 0.648 AC XY: 471157 AN XY: 726636

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.692

Gnomad4 ASJ exome AF: 0.569

Gnomad4 EAS exome AF: 0.851

Gnomad4 SAS exome AF: 0.602

Gnomad4 FIN exome AF: 0.693

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.634

GnomAD4 genome AF: 0.617 AC: 93701 AN: 151810 Hom.: 29448 Cov.: 31 AF XY: 0.621 AC XY: 46074 AN XY: 74156

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.833

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.651

Gnomad4 OTH AF: 0.611

Alfa AF: 0.629 Hom.: 27216

Bravo AF: 0.610

Asia WGS AF: 0.691 AC: 2402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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	- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.71
DANN	Benign	0.41

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: rs4253963; hg19: chr1-216592003;