rs1215540106

Positions:

• chr1-216198561-ATAGT-AC
• chr1-216198561-ATAGT-AT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_206933.4(USH2A):​c.3831_3834delinsG​(p.Leu1278del) variant causes a protein altering change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E1277E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 protein_altering
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.93

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_206933.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-216198562-TAGT-C is Pathogenic according to our data. Variant chr1-216198562-TAGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438019.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.3831_3834delinsG	p.Leu1278del	protein_altering_variant	18/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+2637_691+2640delinsC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.3831_3834delinsG	p.Leu1278del	protein_altering_variant	18/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.3831_3834delinsG	p.Leu1278del	protein_altering_variant	18/21	1
USH2A-AS1	ENST00000420867.1	n.362+2637_362+2640delinsC		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.3831_3834delinsG	p.Leu1278del	protein_altering_variant	18/73

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

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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: rs1215540106; hg19: chr1-216371904;