1-216073258-GC-GATGCCAACTTAA

Position:

• chr1-216073258-GC-GATGCCAACTTAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_206933.4(USH2A):​c.5614delinsTTAAGTTGGCAT​(p.Ala1872LeufsTer64) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1872A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.49

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

Verdict is Pathogenic. Variant got 12 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 1-216073259-C-ATGCCAACTTAA is Pathogenic according to our data. Variant chr1-216073259-C-ATGCCAACTTAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.5614delinsTTAAGTTGGCAT	p.Ala1872LeufsTer64	frameshift_variant	28/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.136+659delinsATGCCAACTTAA		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.136+659delinsATGCCAACTTAA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.5614delinsTTAAGTTGGCAT	p.Ala1872LeufsTer64	frameshift_variant	28/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.136+659delinsATGCCAACTTAA		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2016

The c.5614delGins12 variant in the USH2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Alanine 1872, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Ala1872LeufsX64. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5614delGins12 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.5614delGins12 variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312180; hg19: chr1-216246601;