1-216325569-A-C

Position:

• chr1-216325569-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_206933.4(USH2A):​c.879T>G​(p.Leu293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,342 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (107 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.892

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-216325569-A-C is Benign according to our data. Variant chr1-216325569-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48609.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.879T>G	p.Leu293=	synonymous_variant	6/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.879T>G	p.Leu293=	synonymous_variant	6/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.879T>G	p.Leu293=	synonymous_variant	6/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.879T>G	p.Leu293=	synonymous_variant	6/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.879T>G	p.Leu293=	synonymous_variant	6/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152040 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00555 AC: 1387 AN: 249974 Hom.: 36 AF XY: 0.00497 AC XY: 671 AN XY: 135136

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00691

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.0582

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00233 AC: 3400 AN: 1461184 Hom.: 107 Cov.: 31 AF XY: 0.00231 AC XY: 1676 AN XY: 726912

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0675

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152158 Hom.: 14 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74372

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0647

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000489 Hom.: 0

Bravo AF: 0.00340

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 2A Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 23, 2010

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3767698; hg19: chr1-216498911;