1-215648656-C-T

Position:

• chr1-215648656-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_206933.4(USH2A):​c.14454G>A​(p.Pro4818Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,614,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.29

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-215648656-C-T is Benign according to our data. Variant chr1-215648656-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 177925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215648656-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.14454G>A	p.Pro4818Pro	synonymous_variant	66/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.14454G>A	p.Pro4818Pro	synonymous_variant	66/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.14454G>A	p.Pro4818Pro	synonymous_variant	66/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000879 AC: 221 AN: 251368 Hom.: 0 AF XY: 0.000670 AC XY: 91 AN XY: 135858

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000341 AC: 499 AN: 1461876 Hom.: 4 Cov.: 31 AF XY: 0.000272 AC XY: 198 AN XY: 727238

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74442

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00354

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2010	p.Pro4818Pro in Exon 66 of USH2A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.1% (42/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs137902779). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2019	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	- -

Usher syndrome type 2A Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39 Benign:1

Likely 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	-0.84
CADD	Benign	0.10
DANN	Benign	0.28

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: rs137902779; hg19: chr1-215821998; COSMIC: COSV56365810;