1-216073270-A-C

Position:

• chr1-216073270-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_206933.4(USH2A):​c.5603T>G​(p.Phe1868Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,616 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 8.72

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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 1-216073270-A-C is Pathogenic according to our data. Variant chr1-216073270-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216073270-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-216073270-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.5603T>G	p.Phe1868Cys	missense_variant	28/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.136+670A>C		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.136+670A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.5603T>G	p.Phe1868Cys	missense_variant	28/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.136+670A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727106

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1868 of the USH2A protein (p.Phe1868Cys). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function. ClinVar contains an entry for this variant (Variation ID: 438023). This missense change has been observed in individual(s) with Usher syndrome (PMID: 22135276, 28041643, 29142287). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

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

Uncertain significance, flagged submission

clinical testing

Counsyl

Sep 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.58	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.67		Gain of methylation at K1867 (P = 0.0303);
MVP		0.98
MPC		0.26
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.65

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: rs1553298240; hg19: chr1-216246612;