rs140326085

Positions:

• chr1-216078252-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_206933.4(USH2A):​c.5409C>G​(p.Val1803=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.12

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]

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-216078252-G-C is Benign according to our data. Variant chr1-216078252-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 48532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216078252-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.5409C>G	p.Val1803=	synonymous_variant	27/72	ENST00000307340.8	NP_996816.3
USH2A-AS2	NR_125992.1	n.137-821G>C		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.136+5652G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.5409C>G	p.Val1803=	synonymous_variant	27/72	1	NM_206933.4	ENSP00000305941	P1
USH2A-AS2	ENST00000446411.5	n.137-821G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000646 AC: 162 AN: 250928 Hom.: 0 AF XY: 0.000767 AC XY: 104 AN XY: 135574

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00132 AC: 1933 AN: 1461568 Hom.: 1 Cov.: 32 AF XY: 0.00131 AC XY: 951 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74372

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000725

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000928

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4, BP7 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 24, 2017	p.Val1803Val in exon 27 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 0.1% (148/126184) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org/; dbSNP rs140326085). -

Usher syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	0.32
DANN	Benign	0.75

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: rs140326085; hg19: chr1-216251594;