rs78250390

chr1-215900085-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_206933.4(USH2A):c.7584C>T(p.Thr2528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,542 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.192

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-215900085-G-A is Benign according to our data. Variant chr1-215900085-G-A is described in ClinVar as [Benign]. Clinvar id is 48585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215900085-G-A is described in Lovd as [Benign]. Variant chr1-215900085-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00909 (1383/152154) while in subpopulation AFR AF= 0.0309 (1284/41514). AF 95% confidence interval is 0.0295. There are 15 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7584C>T	p.Thr2528=	synonymous_variant	40/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.7584C>T	p.Thr2528=	synonymous_variant	40/72	1	NM_206933.4	P1
	ENST00000414995.1	n.61-640G>A		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7584C>T	p.Thr2528=	synonymous_variant	40/73

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1371 AN: 152036 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00266 AC: 668 AN: 250780 Hom.: 10 AF XY: 0.00202 AC XY: 274 AN XY: 135502

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00119 AC: 1741 AN: 1461388 Hom.: 29 Cov.: 32 AF XY: 0.00111 AC XY: 810 AN XY: 727004

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00909 AC: 1383 AN: 152154 Hom.: 15 Cov.: 33 AF XY: 0.00866 AC XY: 644 AN XY: 74386

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00499 Hom.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2012	Thr2528Thr in exon 40 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 3.2% (119/3738) of A frican American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS/; dbSNP rs78250390). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2017	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	9.9
Dann	Benign	0.79

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: rs78250390; hg19: chr1-216073427;