rs111033394

Positions:

• chr1-215934786-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):​c.7130A>G​(p.Asn2377Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00423 in 1,610,458 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N2377N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.16

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012489766).
• BP6: Variant 1-215934786-T-C is Benign according to our data. Variant chr1-215934786-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215934786-T-C is described in Lovd as [Likely_benign]. Variant chr1-215934786-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7130A>G	p.Asn2377Ser	missense_variant	38/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7130A>G	p.Asn2377Ser	missense_variant	38/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.7130A>G	p.Asn2377Ser	missense_variant	38/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 580 AN: 152012 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00606

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00392 AC: 981 AN: 250098 Hom.: 8 AF XY: 0.00382 AC XY: 517 AN XY: 135184

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00926

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00427 AC: 6225 AN: 1458328 Hom.: 24 Cov.: 31 AF XY: 0.00410 AC XY: 2973 AN XY: 725236

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000656

Gnomad4 FIN exome AF: 0.00848

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152130 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74368

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00605

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00480

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00395 Hom.: 1

Bravo AF: 0.00327

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00376 AC: 456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is associated with the following publications: (PMID: 25910913, 26927203, 22004887) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2022	Variant summary: USH2A c.7130A>G (p.Asn2377Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 250098 control chromosomes in the gnomAD database, including 8 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0039 vs 0.011), allowing no conclusion about variant significance. Although reported in the literature, to our knowledge, no penetrant association of c.7130A>G in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2012	Asn2377Ser in exon 38 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (35/7016) of European American chromosomes and 0.1% (7/3738) of African American chromosomes in a broad popula tion by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; d bSNP rs111033394). -

Usher syndrome type 2A Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Dec 28, 2016

- -

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.076	T
Sift4G	Benign	0.10	T
Polyphen		0.92	P
Vest4		0.58
MVP		0.87
MPC		0.030
ClinPred		0.046	T
GERP RS		5.8
Varity_R		0.085
gMVP		0.24

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: rs111033394; hg19: chr1-216108128;