1-216198451-A-G

Position:

• chr1-216198451-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_206933.4(USH2A):​c.3945T>C​(p.Asn1315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,006 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (202 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.933

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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-216198451-A-G is Benign according to our data. Variant chr1-216198451-A-G is described in ClinVar as [Benign]. Clinvar id is 48510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216198451-A-G is described in Lovd as [Likely_benign]. Variant chr1-216198451-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.933 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0118 (1802/152224) while in subpopulation SAS AF= 0.0234 (113/4828). AF 95% confidence interval is 0.0199. There are 11 homozygotes in gnomad4. There are 873 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.3945T>C	p.Asn1315=	synonymous_variant	18/72	ENST00000307340.8	NP_996816.3
USH2A-AS1	XR_922596.4	n.691+2526A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.3945T>C	p.Asn1315=	synonymous_variant	18/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.3945T>C	p.Asn1315=	synonymous_variant	18/21	1		ENSP00000355909
USH2A-AS1	ENST00000420867.1	n.362+2526A>G		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.3945T>C	p.Asn1315=	synonymous_variant	18/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1802 AN: 152106 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00999

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0140 AC: 3523 AN: 250934 Hom.: 34 AF XY: 0.0153 AC XY: 2078 AN XY: 135596

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0148 AC: 21702 AN: 1461782 Hom.: 202 Cov.: 32 AF XY: 0.0154 AC XY: 11189 AN XY: 727188

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00930

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0118 AC: 1802 AN: 152224 Hom.: 11 Cov.: 32 AF XY: 0.0117 AC XY: 873 AN XY: 74418

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00999

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0154 Hom.: 9

Bravo AF: 0.0118

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0179

EpiControl AF: 0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
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	Athena Diagnostics	Jan 23, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2010	Asn1315Asn in exon 18 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction and is found at an equal frequency in probands and controls (W eston 2000, Leroy 2001, Pennings 2004). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2011	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+	-	- -

Usher syndrome type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinitis pigmentosa Benign:1

Benign, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.1
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41303257; hg19: chr1-216371793; COSMIC: COSV56346147; COSMIC: COSV56346147;