rs41315579

Variant names:

• chr1-215900872-G-A
• rs41315579
• NM_206933.4:c.7334C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-215900872-G-A
• chr1-215900872-G-C
• chr1-215900872-G-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 variant NM_206933.4:c.7334C>T in USH2A is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 2445 (p.Ser2445Phe). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0054 (489/91072 alleles, 3 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss USH2A threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.358, which meets no codes. This variant was reported in one individual with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 28041643, 33926394). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143592/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:4 B:6
• Conservation: PhyloP100: 7.68
• 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 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

ENSG00000229242 (HGNC:):

ACMG classification

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.7334C>T	p.Ser2445Phe	missense	Exon 39 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.7334C>T	p.Ser2445Phe	missense	Exon 39 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.7334C>T	p.Ser2445Phe	missense	Exon 39 of 73	ENSP00000501296.1	O75445-3
	ENSG00000229242	ENST00000414995.1	TSL:3	n.208G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000841 AC: 211 AN: 250880 AF XY: 0.00111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000357 AC: 522 AN: 1461440 Hom.: 3 Cov.: 31 AF XY: 0.000517 AC XY: 376 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000671 AC: 3 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00530 AC: 457 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5730

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111744

Other (OTH) AF: 0.000580 AC: 35 AN: 60356

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.46		Loss of glycosylation at S2445 (P = 0.0094)
MVP		0.98
MPC		0.24
ClinPred		0.16	T
GERP RS		6.0
Varity_R		0.24
gMVP		0.39
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs41315579; hg19: chr1-216074214;