rs201026468

chr1-216073175-A-Cchr1-216073175-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM5 BP4_Moderate

The NM_206933.4(USH2A):c.5698T>G(p.Cys1900Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,870 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign 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. C1900R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B: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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Fibronectin type-III 5 (size 86) in uniprot entity USH2A_HUMAN there are 20 pathogenic changes around while only 4 benign (83%) in NM_206933.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-216073174-C-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.07363734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.5698T>G	p.Cys1900Gly	missense_variant	28/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.136+575A>C		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.136+575A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.5698T>G	p.Cys1900Gly	missense_variant	28/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.136+575A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000479 AC: 120 AN: 250564 Hom.: 1 AF XY: 0.000672 AC XY: 91 AN XY: 135412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461632 Hom.: 4 Cov.: 31 AF XY: 0.000318 AC XY: 231 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00332

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000440 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000503 AC: 61

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The USH2A p.C1900G variant was identified in a homozygous individual with Usher syndrome, as well as a heterozygous individual with retinitis pigmentosa (Bonnet_2016_PMID: 27460420; Haer-Wigman_2017_PMID: 28224992). The variant was identified in dbSNP (ID: rs201026468) and in ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and Counsyl; and as likely benign by Invitae). The variant was identified in control databases in 120 of 250564 chromosomes (1 homozygous) at a frequency of 0.0004789, and was observed at the highest frequency in the South Asian population in 117 of 30610 chromosomes (1 homozygous) (freq: 0.003822) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.C1900 residue is conserved in mammals and more distantly related organisms, however computational analyses predicting the impact of this variant on protein function are not available. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2019	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: USH2A c.5698T>G (p.Cys1900Gly) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 250564 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00048 vs 0.011), allowing no conclusion about variant significance. c.5698T>G has been reported in the literature as non-informative genotypes in individuals affected with and/or undergoing diagnostic exome sequencing for Usher Syndrome/visual impairment (example, Bonnet_2016, Haer-Wigman_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 27, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Cys1900Gly va riant in USH2A has been reported as a homozygous variant in one individual with Usher syndrome, who was also homozygous for another variant of uncertain clinica l significance in USH2A (Bonnet 2016). The variant was also reported in two indi viduals with hearing loss and one individual with retinitis pigmentosa; however these individuals were heterozygous for the variant and did not carry a second v ariant (Haer-Wigman 2017, unpublished LMM data, ClinVar Variation ID: 4853). Thi s variant has also been identified in 0.38% (117/30776) of South Asian chromosom es, including one homozygous individual, by the genome Aggregation Database (gno mAD,http://gnomad.broadinstitute.org; dbSNP rs201026468). Computational predicti on tools and conservation analysis suggest that this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the p.Cys1900Gly variant is unc ertain, these data suggest that it is more likely to be benign. -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 01, 2021

NM_206933.2(USH2A):c.5698T>G(C1900G) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. C1900G has been observed in cases with relevant disease (PMID: 28224992, 27460420). Functional assessments of this variant are not available in the literature. C1900G has been observed in population frequency databases (gnomAD: SAS 0.38%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.5698T>G(C1900G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.54		Gain of disorder (P = 0.0032);
MVP		0.90
MPC		0.25
ClinPred		0.22	T
GERP RS		5.9
Varity_R		0.90
gMVP		0.83

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: rs201026468; hg19: chr1-216246517;