rs55713064

chr1-215878724-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):c.8558+40C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00991 in 1,592,782 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (96 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00500

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-215878724-G-T is Benign according to our data. Variant chr1-215878724-G-T is described in ClinVar as [Benign]. Clinvar id is 403599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215878724-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.8558+40C>A		intron_variant		ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.8558+40C>A		intron_variant		1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.8558+40C>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1163 AN: 152104 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00859 AC: 2036 AN: 236936 Hom.: 18 AF XY: 0.00875 AC XY: 1120 AN XY: 127990

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00777

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00358

Gnomad FIN exome AF: 0.00666

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0101 AC: 14617 AN: 1440560 Hom.: 96 Cov.: 28 AF XY: 0.0103 AC XY: 7363 AN XY: 716712

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00815

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.00633

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00956

GnomAD4 genome AF: 0.00764 AC: 1163 AN: 152222 Hom.: 8 Cov.: 32 AF XY: 0.00750 AC XY: 558 AN XY: 74422

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00472

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0101 Hom.: 2

Bravo AF: 0.00800

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency too high for disorder - 1.4% of European chromosomes in ExAC -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.3
Dann	Benign	0.57

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: rs55713064; hg19: chr1-216052066;