1-216084853-C-T

Variant names:

• chr1-216084853-C-T
• rs727505116
• NM_206933.4:c.5012G>A

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1_Strong PP3 PM3

This summary comes from the ClinGen Evidence Repository: The c.5012G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 1671 (p.Gly1671Asp). The highest population minor allele frequency in gnomAD v4 is 0.04% (51/91074 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 10 individuals with retinitis pigmentosa or inherited retinal disease. Of those individuals, 9 were homozygous and 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.4251+1G>T, 5 PM3 points, PMID:26667666, 32581362, 33749171, 38219857, PM3_VeryStrong). Internal evidence from one laboratory indicates that this variant has been observed in trans with a likely pathogenic missense variant in an individual with optic neuropathy, night blindness, and sensorineural hearing loss and homozygous in one individual with hearing loss and hyperopia (Personal communication, SCV001789135.4). This suggests that there may be phenotypic variability with some individuals presenting with isolated retinal dystrophy, and some presenting with hearing loss and signs and/or symptoms of retinal dystrophy. Of note, many of these individuals were of South Asian ancestry, consistent with the population evidence from gnomAD (PMID:38219857). The variant has been reported to segregate with inherited retinal disease in 3 affected family members from 2 families (PP1_Strong; PMID:38219857). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive USH2A-related inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_VeryStrong, PP1_Strong. (ClinGen Hearing Loss VCEP specifications version 2, 02.27.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA185105/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:2
• Conservation: PhyloP100: 6.54
• Publications: 3 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Pathogenic. The variant received 7 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.5012G>A	p.Gly1671Asp	missense	Exon 25 of 72	NP_996816.3
	USH2A-AS2	NR_125992.1		n.266-1869C>T		intron	N/A
	USH2A-AS2	NR_125993.1		n.137-1869C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5012G>A	p.Gly1671Asp	missense	Exon 25 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.5012G>A	p.Gly1671Asp	missense	Exon 25 of 73	ENSP00000501296.1
	USH2A	ENST00000463147.1	TSL:2	n.256G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000479 AC: 12 AN: 250622 AF XY: 0.0000738

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: 0.0000342 AC: 50 AN: 1460998 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 726808

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111490

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.87		Gain of ubiquitination at K1674 (P = 0.1317)
MVP		0.82
MPC		0.26
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.96
Mutation Taster		=2/98	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: rs727505116; hg19: chr1-216258195;