rs111033367

Variant names:

• chr1-216190279-CAG-C
• rs111033367
• NM_206933.4:c.4338_4339delCT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP1_Moderate PM2 PVS1 PP4 PM3

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID:9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID:20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID:9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA252228/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: USH2A ENST00000307340.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:1
• Conservation: PhyloP100: 7.84
• Publications: 14 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 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307340.8. 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.4338_4339delCT	p.Cys1447GlnfsTer29	frameshift	Exon 20 of 72	NP_996816.3
	USH2A	NM_007123.6		c.4338_4339delCT	p.Cys1447GlnfsTer29	frameshift	Exon 20 of 21	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4338_4339delCT	p.Cys1447GlnfsTer29	frameshift	Exon 20 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.4338_4339delCT	p.Cys1447GlnfsTer29	frameshift	Exon 20 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.4338_4339delCT	p.Cys1447GlnfsTer29	frameshift	Exon 20 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250692 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460590 Hom.: 0 AF XY: 0.0000193 AC XY: 14 AN XY: 726642

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111202

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74138

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Retinitis pigmentosa 39 (3)
3	-	-	USH2A-related disorder (4)
2	-	-	not provided (2)
2	-	-	Usher syndrome type 2A (2)
1	-	-	Retinal dystrophy (1)
1	-	-	Usher syndrome (1)
1	-	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs111033367; hg19: chr1-216363621;