1-216073258-GC-GATGCCAAGTTAA

Variant names:

• chr1-216073259-C-ATGCCAAGTTAA
• rs869312180
• NM_206933.4:c.5614delGinsTTAACTTGGCAT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_206933.4(USH2A):​c.5614delGinsTTAACTTGGCAT​(p.Ala1872LeufsTer64) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as 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, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.49
• Publications: 2 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-216073259-C-ATGCCAAGTTAA is Pathogenic according to our data. Variant chr1-216073259-C-ATGCCAAGTTAA is described in ClinVar as Pathogenic. ClinVar VariationId is 224746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.5614delGinsTTAACTTGGCAT	p.Ala1872LeufsTer64	frameshift missense	Exon 28 of 72	NP_996816.3
	USH2A-AS2	NR_125992.1		n.136+659delCinsATGCCAAGTTAA		intron	N/A
	USH2A-AS2	NR_125993.1		n.136+659delCinsATGCCAAGTTAA		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5614delGinsTTAACTTGGCAT	p.Ala1872LeufsTer64	frameshift missense	Exon 28 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.5614delGinsTTAACTTGGCAT	p.Ala1872LeufsTer64	frameshift missense	Exon 28 of 73	ENSP00000501296.1
	USH2A-AS2	ENST00000430890.5	TSL:2	n.78+453delCinsATGCCAAGTTAA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Retinitis pigmentosa 39 (2)
2	-	-	Usher syndrome type 2A (2)
1	-	-	Retinal dystrophy (1)
-	-	-	USH2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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

Other links and lift over

dbSNP: rs869312180; hg19: chr1-216246601;