rs201386640

Variant names:

• chr1-215965376-C-G
• rs201386640
• NM_206933.4:c.7061G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-215965376-C-G
• chr1-215965376-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_206933.4(USH2A):​c.7061G>C​(p.Arg2354Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2354C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26294196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7061G>C	p.Arg2354Pro	missense_variant	Exon 37 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7061G>C	p.Arg2354Pro	missense_variant	Exon 37 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.7061G>C	p.Arg2354Pro	missense_variant	Exon 37 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2354 of the USH2A protein (p.Arg2354Pro). This variant is present in population databases (rs201386640, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1506557). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.14
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.18	T
Sift4G	Benign	0.091	T
Polyphen		0.56	P
Vest4		0.42
MutPred		0.55		Loss of MoRF binding (P = 0.0345);
MVP		0.85
MPC		0.067
ClinPred		0.13	T
GERP RS		-5.7
Varity_R		0.26
gMVP		0.60
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201386640; hg19: chr1-216138718;