chr1-216198494-C-A

Variant names:

• chr1-216198494-C-A
• rs111033524
• NM_206933.4:c.3902G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (≥0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143472/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign reviewed by expert panel P:3 U:3 B:11
• Conservation: PhyloP100: 4.83
• 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: Benign. The variant received -8 ACMG points.

• BA1: 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.3902G>T	p.Gly1301Val	missense	Exon 18 of 72	NP_996816.3
	USH2A	NM_007123.6		c.3902G>T	p.Gly1301Val	missense	Exon 18 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.3902G>T	p.Gly1301Val	missense	Exon 18 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.3902G>T	p.Gly1301Val	missense	Exon 18 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.3902G>T	p.Gly1301Val	missense	Exon 18 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000833 AC: 209 AN: 250898 AF XY: 0.00114

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000419 AC: 613 AN: 1461764 Hom.: 4 Cov.: 32 AF XY: 0.000589 AC XY: 428 AN XY: 727178

African (AFR) AF: 0.000119 AC: 4 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

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

South Asian (SAS) AF: 0.00511 AC: 441 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111948

Other (OTH) AF: 0.000580 AC: 35 AN: 60390

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.92
MVP		0.96
MPC		0.19
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.50
gMVP		0.78
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs111033524; hg19: chr1-216371836;