chr1-215900194-G-T

Variant names:

• chr1-215900194-G-T
• rs483353056
• NM_206933.4:c.7475C>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_206933.4(USH2A):​c.7475C>A​(p.Ser2492*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,286 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. S2492S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH2A NM_206933.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.91

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]

ENSG00000229242 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-215900194-G-T is Pathogenic according to our data. Variant chr1-215900194-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7475C>A	p.Ser2492*	stop_gained	Exon 40 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7475C>A	p.Ser2492*	stop_gained	Exon 40 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.7475C>A	p.Ser2492*	stop_gained	Exon 40 of 73			ENSP00000501296.1
ENSG00000229242	ENST00000414995.1	n.61-531G>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461286 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2

-

Molecular Genetics Laboratory; Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 24, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S2492X nonsense variant in the USH2A gene is predicted to cause loss of normal protein functioneither through protein truncation or nonsense-mediated mRNA decay. S2492X was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. Although thisvariant has not been reported previously to our knowledge, we consider it to be pathogenic. -

Retinitis pigmentosa 39 Pathogenic:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.88
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs483353056; hg19: chr1-216073536;