rs869312182

chr1-216000442-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_206933.4(USH2A):c.6446C>A(p.Pro2149Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P2149P) has been classified as Likely benign.

• 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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 1-216000442-G-T is Pathogenic according to our data. Variant chr1-216000442-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224753.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-216000442-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.6446C>A	p.Pro2149Gln	missense_variant	33/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.6446C>A	p.Pro2149Gln	missense_variant	33/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.6446C>A	p.Pro2149Gln	missense_variant	33/73

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

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

May 26, 2020

The c.6446C>A (p.Pro2149Gln) variant in USH2A was absent from gnomAD (PM2). It has been detected in one patient with Usher syndrome and one patient with isolated Retinitis pigmentosa, both of whom carried another suspected pathogenic variant in trans (PM3_Strong; PP4; PMIDs: 26872967, 29074561, 28041643; ClinVar ID: 2356). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PM3_Strong, PP4. -

Usher syndrome type 2A Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Aug 28, 2015

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

-

- -

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
MutationTaster	Benign	1.0	D;D
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;