chr1-215675037-T-C

Variant names:

• chr1-215675037-T-C
• rs397517984
• NM_206933.4:c.12874A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3_Strong PP3 PP1

This summary comes from the ClinGen Evidence Repository: The c.12874A>G variant in USH2A is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 4292 (p.Asn4292Asp). The highest population frequency in gnomAD v4.1.0 is 0.02% (20/86258 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.707, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been identified in at least 6 individuals with apparently isolated retinal dystrophy. One individual was homozygous, one was heterozygous for a second variant of uncertain significance, three had a second pathogenic variant with phase unknown, and one harbored a second pathogenic variant confirmed in trans (2 points, PM3_Strong, PMID:28041643, 25133751, 37322672, Invitae Internal evidence SCV001403886.5, Blueprint Genetics internal evidence SCV001240918.1). The variant has been reported to segregate with retinal dystrophy in 1 affected family member from 1 family (PP1; PMID:25133751). Of note, hearing loss was not reported in any of these individuals, indicating that this variant is likely causative for isolated retinal dystrophy and not Usher syndrome. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_Strong, PP1. (Hearing loss VCEP specifications version 2; 05.15.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143304/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:3
• Conservation: PhyloP100: 4.85
• Publications: 4 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

Our verdict: Likely_pathogenic. The variant received 6 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.
• PP3: 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.12874A>G	p.Asn4292Asp	missense	Exon 63 of 72	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.12874A>G	p.Asn4292Asp	missense	Exon 63 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.12874A>G	p.Asn4292Asp	missense	Exon 63 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251114 AF XY: 0.0000368

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461878 Hom.: 0 Cov.: 37 AF XY: 0.0000179 AC XY: 13 AN XY: 727242

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: 39696

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.9
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.67		Loss of glycosylation at P4287 (P = 0.1314)
MVP		0.94
MPC		0.24
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.36
gMVP		0.77
Mutation Taster		=4/96	disease causing

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: rs397517984; hg19: chr1-215848379;