rs200038092

chr1-215965369-A-Cchr1-215965369-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5 BP4_Strong

The NM_206933.4(USH2A):c.7068T>G(p.Asn2356Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,613,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2356S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 0.781

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 Likely_benign. Variant got -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215965370-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988656.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014531165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7068T>G	p.Asn2356Lys	missense_variant	37/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.7068T>G	p.Asn2356Lys	missense_variant	37/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.7068T>G	p.Asn2356Lys	missense_variant	37/73

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000784 AC: 197 AN: 251316 Hom.: 0 AF XY: 0.000736 AC XY: 100 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0104

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000310 AC: 453 AN: 1461618 Hom.: 4 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00926

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000563

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30073356, 30245029, 23591405, 25356976, 24938718, 25078356, 24853665, 23967202, 26346818, 29625443, 30804660, 32090030, 33105608, 34426522, 33691693, 33090715, 33124170, 35114279, 35860547, 32188678, 32675063, 35836572, 30826590) -

Usher syndrome type 2A Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2022	Variant summary: USH2A c.7068T>G (p.Asn2356Lys) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 291028 control chromosomes, predominantly at a frequency of 0.01 within the East Asian subpopulation in the gnomAD database and has also been reported as a common variant in the Japanese normal hearing population (example, Moteki_2016). This frequency is close to or almost similar (i.e., not significantly lower) than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.01 in East Asian cohorts vs 0.011), supporting a benign outcome. In a cross sectional ascertainment spanning 2013-2021, c.7068T>G has been reported in the literature as a VUS and/or non-informative genotype in settings of multigene panel testing predominantly among East Asian cohorts of individuals with a variety of Usher syndrome related manifestations such as hearing loss (example, Miyagawa_2013), sporadic retinal dystrophy (example, Glockle_2014), Inherited Retinal Degeneration cohort (example, Huang_2015), Japanese Normal Hearing cohort (Moteki_2016), Usher syndrome cohort (example, Galli-Resta_2018, Meng_2021), an individual with Usher syndrome compound heterozygous for causative variants in the MYO7A gene (example, Li_2019), possible digenic association proposed in an individual with Inherited Retinal Degeneration (example, Liu_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.95	P
Vest4		0.61
MutPred		0.57		Gain of methylation at N2356 (P = 0.0325);
MVP		0.90
MPC		0.21
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.19
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200038092; hg19: chr1-216138711;