rs878853412

Positions:

• chr1-216048579-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_206933.4(USH2A):​c.6118T>G​(p.Cys2040Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,822 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2040R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 7.43

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 1-216048579-A-C is Pathogenic according to our data. Variant chr1-216048579-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236543.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.6118T>G	p.Cys2040Gly	missense_variant	31/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.6118T>G	p.Cys2040Gly	missense_variant	31/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.6118T>G	p.Cys2040Gly	missense_variant	31/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727208

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: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal dystrophy Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 08, 2019	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 08, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2040 of the USH2A protein (p.Cys2040Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 27208204, 28041643). ClinVar contains an entry for this variant (Variation ID: 236543). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

Retinitis pigmentosa 39 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 18, 2023

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 24, 2017

- -

Usher syndrome type 2A Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 27, 2021

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.96
MPC		0.25
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.61
gMVP		0.74

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: rs878853412; hg19: chr1-216221921;