rs786200928

Variant names:

• chr1-215891198-T-C
• rs786200928
• NM_206933.4:c.7595-2144A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_206933.4(USH2A):​c.7595-2144A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001442777: At least one publication reports experimental evidence that this variant activates a pseudoexon, resulting in aberrant splicing (e.g. Vache_2011)." and additional evidence is available in ClinVar. The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.000059 (0 hom., cov: 32)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 1.94
• Publications: 55 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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000229242 (HGNC:):

ACMG classification

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001442777: At least one publication reports experimental evidence that this variant activates a pseudoexon, resulting in aberrant splicing (e.g. Vache_2011).; SCV000955192: Studies have shown that this variant results in an insertion of 152bp at the junction of exons 40 and 41, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22009552).; SCV001780430: functional studies demonstrated an insertion of 152 bp at the junction of exons 40 and 41, leading to an out-of-frame protein with premature stop codon in exon 41 (designated p.K2532TfsX56) (Vache et al., 2012; Steele-Stallard et al., 2013); SCV005356597: RNA analysis of nasal cells from one affected individual confirmed that this variant creates a pseudoexon (Vaché et al. 2012. PubMed ID: 22009552).; SCV004847503: RNA samples from these patients showed abnormal splicing predicted to lead to an abnormal or absent protein.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-215891198-T-C is Pathogenic according to our data. Variant chr1-215891198-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30722.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.7595-2144A>G		intron	N/A	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.7595-2144A>G		intron	N/A	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.7595-2144A>G		intron	N/A	ENSP00000501296.1	O75445-3
	ENSG00000229242	ENST00000414995.1	TSL:3	n.60+4557T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74488

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000680

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
5	-	-	Usher syndrome type 2A (5)
3	-	-	Retinitis pigmentosa 39 (3)
3	-	-	Usher syndrome (3)
2	-	-	Retinal dystrophy (2)
2	-	-	USH2A-related disorder (3)
2	-	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (2)
1	-	-	Rare genetic deafness (1)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Usher syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	29
DANN	Benign	0.89
PhyloP100		1.9
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 1

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

Other links and lift over

dbSNP: rs786200928; hg19: chr1-216064540;