NM_206933.4:c.956G>A

Variant names:

• chr1-216325492-C-T
• rs121912599
• NM_206933.4:c.956G>A

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PP1 PP4 PM3

This summary comes from the ClinGen Evidence Repository: The c.956G>A variant in USH2A is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 319. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002679 (15/34508 alleles) in the Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.524, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. At least one patient was homozygous for this variant and displayed moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10729113). This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID:26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong). One of the individuals who was compound heterozygous for the variant and another pathogenic variant in USH2A (RCV000599950.1), had an affected sibling in whom both variants segregated (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP4, PM3_VS, PP1 (Hearing Loss VCEP specifications version 2; 6/15/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA252231/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 7.52
• Publications: 11 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

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 4 ACMG points.

• 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: 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.956G>A	p.Cys319Tyr	missense	Exon 6 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.956G>A	p.Cys319Tyr	missense	Exon 6 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.956G>A	p.Cys319Tyr	missense	Exon 6 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.956G>A	p.Cys319Tyr	missense	Exon 6 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.956G>A	p.Cys319Tyr	missense	Exon 6 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250870 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000358 AC: 16 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000925 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		Gain of phosphorylation at C319 (P = 0.0502)
MVP		0.92
MPC		0.28
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	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: rs121912599; hg19: chr1-216498834;