1-216200031-C-T

Variant names:

• chr1-216200031-C-T
• rs483353055
• NM_206933.4:c.3407G>A

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PP4 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID:22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA269917/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.84
• Publications: 7 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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: 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.3407G>A	p.Ser1136Asn	missense	Exon 17 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.3407G>A	p.Ser1136Asn	missense	Exon 17 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.3407G>A	p.Ser1136Asn	missense	Exon 17 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.3407G>A	p.Ser1136Asn	missense	Exon 17 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.3407G>A	p.Ser1136Asn	missense	Exon 17 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Usher syndrome type 2A (3)
1	-	-	Cone-rod dystrophy (1)
1	-	-	not provided (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
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.66		Loss of disorder (P = 0.105)
MVP		0.93
MPC		0.22
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.52
gMVP		0.73
Mutation Taster		=2/98	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: rs483353055; hg19: chr1-216373373;