1-215675299-T-C

Position:

• chr1-215675299-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.12612A>G​(p.Thr4204Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 1,613,914 control chromosomes in the GnomAD database, including 503,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43060 hom., cov: 33)
  • Exomes 𝑓: 0.79 (460076 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.101

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=-0.83).
• BP6: Variant 1-215675299-T-C is Benign according to our data. Variant chr1-215675299-T-C is described in ClinVar as [Benign]. Clinvar id is 177993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.12612A>G	p.Thr4204Thr	synonymous_variant	63/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.12612A>G	p.Thr4204Thr	synonymous_variant	63/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.12612A>G	p.Thr4204Thr	synonymous_variant	63/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113712 AN: 152030 Hom.: 43036 Cov.: 33

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.786

GnomAD3 exomes AF: 0.767 AC: 191133 AN: 249244 Hom.: 73901 AF XY: 0.767 AC XY: 103433 AN XY: 134862

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.797

Gnomad EAS exome AF: 0.647

Gnomad SAS exome AF: 0.695

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.812

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.792 AC: 1157157 AN: 1461764 Hom.: 460076 Cov.: 89 AF XY: 0.789 AC XY: 574029 AN XY: 727172

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.808

Gnomad4 ASJ exome AF: 0.788

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.752

Gnomad4 NFE exome AF: 0.812

Gnomad4 OTH exome AF: 0.777

GnomAD4 genome AF: 0.748 AC: 113790 AN: 152150 Hom.: 43060 Cov.: 33 AF XY: 0.744 AC XY: 55328 AN XY: 74384

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.785

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.680

Gnomad4 FIN AF: 0.744

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.787

Alfa AF: 0.798 Hom.: 85033

Bravo AF: 0.747

Asia WGS AF: 0.654 AC: 2274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 273/386 (LMM data) -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	-	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

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	-0.83
CADD	Benign	0.36
DANN	Benign	0.36

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: rs2797235; hg19: chr1-215848641; COSMIC: COSV56342874;