1-216046570-T-G

Position:

• chr1-216046570-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The ENST00000307340.8(USH2A):​c.6186A>C​(p.Pro2062=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,613,886 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2062P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (10 hom.)
• Consequence: USH2A ENST00000307340.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.558

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-216046570-T-G is Benign according to our data. Variant chr1-216046570-T-G is described in ClinVar as [Benign]. Clinvar id is 227144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216046570-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.558 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.6186A>C	p.Pro2062=	synonymous_variant	32/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.6186A>C	p.Pro2062=	synonymous_variant	32/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.6186A>C	p.Pro2062=	synonymous_variant	32/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000820 AC: 206 AN: 251300 Hom.: 3 AF XY: 0.00126 AC XY: 171 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000443 AC: 648 AN: 1461578 Hom.: 10 Cov.: 34 AF XY: 0.000657 AC XY: 478 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00630

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000755 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely 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	GeneDx	Jan 09, 2019	This variant is associated with the following publications: (PMID: 20507924) -
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 12, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2016

p.Pro2062Pro in exon 32 of USH2A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.6% (98/16508) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs200247886). -

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	-0.43
CADD	Benign	6.4
DANN	Benign	0.78

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: rs200247886; hg19: chr1-216219912;