rs150982499

Variant names:

• chr1-216084826-T-C
• rs150982499
• NM_206933.4:c.5039A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM3_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.5039A>G (p.Lys1680Arg) variant in USH2A is a missense variant that replaces lysine with arginine at codon 1680. (Add gnomad information) The REVEL score for this variant is 0.252, which does not meet the threshold for PP3. This variant has been observed in the homozygous state in one individual with a clinical diagnosis of Usher syndrome (PMID:36909829), meeting PM3_Supporting. The phenotype observed is highly specific for Usher syndrome, meeting PP4. In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Supporting, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA179559/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:1
• Conservation: PhyloP100: 2.19
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.5039A>G	p.Lys1680Arg	missense	Exon 25 of 72	NP_996816.3	O75445-1
	USH2A-AS2	NR_125992.1		n.266-1896T>C		intron	N/A
	USH2A-AS2	NR_125993.1		n.137-1896T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5039A>G	p.Lys1680Arg	missense	Exon 25 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.5039A>G	p.Lys1680Arg	missense	Exon 25 of 73	ENSP00000501296.1	O75445-3
	USH2A	ENST00000463147.1	TSL:2	n.283A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250788 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461240 Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 65 AN XY: 726916

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.000560 AC: 25 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

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

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111638

Other (OTH) AF: 0.000298 AC: 18 AN: 60358

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	Usher syndrome (2)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.25
Sift	Benign	0.28	T
Sift4G	Benign	0.24	T
Polyphen		0.54	P
Vest4		0.28
MVP		0.90
MPC		0.043
ClinPred		0.14	T
GERP RS		4.9
Varity_R		0.095
gMVP		0.34
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150982499; hg19: chr1-216258168;