rs397518031

Positions:

• chr1-215900217-C-A
• chr1-215900217-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000307340.8(USH2A):​c.7452G>T​(p.Glu2484Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. E2484K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: USH2A ENST00000307340.8 missense, splice_region
• Scores: Splicing: ADA: 0.1614
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.207

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19652387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7452G>T	p.Glu2484Asp	missense_variant, splice_region_variant	40/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7452G>T	p.Glu2484Asp	missense_variant, splice_region_variant	40/72	1	NM_206933.4	ENSP00000305941	P1
	ENST00000414995.1	n.61-508C>A		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7452G>T	p.Glu2484Asp	missense_variant, splice_region_variant	40/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461078 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 08, 2011

The Glu2484Asp variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong supp ort for or against pathogenicity. Although this variant also occurs within the s plice consensus sequence, it does not predict a significant enough impact to the splice sequence to assume it is pathogenic. In summary, the clinical significan ce of this variant cannot be determined with certainty at this time. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 31, 2017

- -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	N
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.049
Sift	Benign	0.34	T
Sift4G	Benign	0.20	T
Polyphen		0.011	B
Vest4		0.17
MutPred		0.51		Gain of phosphorylation at T2479 (P = 0.185);
MVP		0.88
MPC		0.030
ClinPred		0.052	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397518031; hg19: chr1-216073559;