1-216084863-CT-CTT

Variant names:

• chr1-216084863-C-CT
• rs397518018
• NM_206933.4:c.5001dupA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_206933.4(USH2A):​c.5001dupA​(p.Gly1668ArgfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.661
• Publications: 1 publications found

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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-216084863-C-CT is Pathogenic according to our data. Variant chr1-216084863-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 48526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.5001dupA	p.Gly1668ArgfsTer30	frameshift_variant	Exon 25 of 72	ENST00000307340.8	NP_996816.3
USH2A-AS2	NR_125992.1	n.266-1854dupT		intron_variant	Intron 2 of 2
USH2A-AS2	NR_125993.1	n.137-1854dupT		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.5001dupA	p.Gly1668ArgfsTer30	frameshift_variant	Exon 25 of 72	1	NM_206933.4	ENSP00000305941.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:1

Jan 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Mar 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly1668fs variant in USH2A has not been reported in the literature nor previ ously identified by our laboratory. This frameshift variant is predicted to alte r the protein?s amino acid sequence beginning at position 1668 and lead to a pre mature termination codon 30 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Therefore, this variant meets ou r criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397518018; hg19: chr1-216258205;