rs111033472

Positions:

• chr1-216000519-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 ENST00000307340.8(USH2A):​c.6369C>T​(p.Cys2123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,613,642 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: USH2A ENST00000307340.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-216000519-G-A is Benign according to our data. Variant chr1-216000519-G-A is described in ClinVar as [Benign]. Clinvar id is 48560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216000519-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2176/152268) while in subpopulation AFR AF= 0.0485 (2014/41554). AF 95% confidence interval is 0.0467. There are 51 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.6369C>T	p.Cys2123=	synonymous_variant	33/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.6369C>T	p.Cys2123=	synonymous_variant	33/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.6369C>T	p.Cys2123=	synonymous_variant	33/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2164 AN: 152150 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00409 AC: 1028 AN: 251064 Hom.: 21 AF XY: 0.00324 AC XY: 439 AN XY: 135682

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00176 AC: 2568 AN: 1461374 Hom.: 38 Cov.: 31 AF XY: 0.00155 AC XY: 1130 AN XY: 726988

Gnomad4 AFR exome AF: 0.0503

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.0143 AC: 2176 AN: 152268 Hom.: 51 Cov.: 32 AF XY: 0.0146 AC XY: 1084 AN XY: 74454

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00709 Hom.: 12

Bravo AF: 0.0165

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2011

Cys2123Cys in exon 33 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction and has been identified in 1.7% (77/4550) of control chromosom es (dbSNP rs111033472). -

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	-0.48
CADD	Benign	4.3
DANN	Benign	0.61

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: rs111033472; hg19: chr1-216173861;