rs869312182

Variant names:

• chr1-216000442-G-T
• rs869312182
• NM_206933.4:c.6446C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PM3_Strong PP4

This summary comes from the ClinGen Evidence Repository: The c.6446C>A (p.Pro2149Gln) variant in USH2A is a missense variant predicted to cause a substitution of proline by glutamine at amino acid 2149. This variant has been detected in 2 individuals with Usher syndrome. Both were compound heterozygotes for the variant and a pathogenic or likely pathogenic variant and 1 of those were confirmed in trans by parental testing (PMID : 29074561, 31836858). This variant has also been detected in two individuals with isolated retinitis pigmentosa without hearing loss or without additional information about their hearing status . Both were compound heterozygotes for this variant and a pathogenic alteration (PMID : 38219857 ; 28041643). Clingen HL VCEP group agreed to take into consideration two index cases reported with isolated RP, compound heterozygote for this variant and the well known pathogenic c.2276G>A alteration, allowing to PM3_Srong criteria. At least one individual has a phenotype of hearing loss and retinitis pigmentosa, which is consistent with Usher syndrome type II (PP4 ; PMID:32176120). The filtering allele frequency (the lower threshold of the 95% CI) of the c.6446C>A (p.Pro2149Gln) is 0.0002620% chromosomes by gnomAD v4.1.0 (non-Finnish Europeans), which meets the ClinGen Hearing Loss VCEP threshold ≤ 0.007% for PM2_P. The computational predictor REVEL gives a score of 0.36, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A-related conditions (isolated RP and Usher syndrome type II) based on the ACMG/AMP criteria applied, as specified by the Clingen Hearing Loss Expert Panel : PM2_Supporting, PM3_Strong, PP4_Supporting. (Hearing Loss VCEP specifications version 2; 01/15/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA354063/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 6.28

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:1

Jan 15, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.6446C>A (p.Pro2149Gln) variant in USH2A is a missense variant predicted to cause a substitution of proline by glutamine at amino acid 2149. This variant has been detected in 2 individuals with Usher syndrome. Both were compound heterozygotes for the variant and a pathogenic or likely pathogenic variant and 1 of those were confirmed in trans by parental testing (PMID : 29074561, 31836858). This variant has also been detected in two individuals with isolated retinitis pigmentosa without hearing loss or without additional information about their hearing status . Both were compound heterozygotes for this variant and a pathogenic alteration (PMID : 38219857 ; 28041643). Clingen HL VCEP group agreed to take into consideration two index cases reported with isolated RP, compound heterozygote for this variant and the well known pathogenic c.2276G>A alteration, allowing to PM3_Srong criteria. At least one individual has a phenotype of hearing loss and retinitis pigmentosa, which is consistent with Usher syndrome type II (PP4 ; PMID: 32176120). The filtering allele frequency (the lower threshold of the 95% CI) of the c.6446C>A (p.Pro2149Gln) is 0.0002620% chromosomes by gnomAD v4.1.0 (non-Finnish Europeans), which meets the ClinGen Hearing Loss VCEP threshold ≤ 0.007% for PM2_P. The computational predictor REVEL gives a score of 0.36, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A-related conditions (isolated RP and Usher syndrome type II) based on the ACMG/AMP criteria applied, as specified by the Clingen Hearing Loss Expert Panel : PM2_Supporting, PM3_Strong, PP4_Supporting. (Hearing Loss VCEP specifications version 2; 01/15/2025). -

Usher syndrome type 2A Pathogenic:1

Aug 28, 2015

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinal dystrophy Uncertain:1

-

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.34		Loss of glycosylation at S2148 (P = 0.08);
MVP		0.95
MPC		0.23
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312182; hg19: chr1-216173784;