rs35730265

Variant names:

• chr1-216323590-C-G
• rs35730265
• NM_206933.4:c.1434G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-216323590-C-G
• chr1-216323590-C-T
• chr1-216323590-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_206933.4(USH2A):​c.1434G>C​(p.Glu478Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,512 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E478E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 31)
  • Exomes 𝑓: 0.016 (235 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.0430
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007865071).
• BP6: Variant 1-216323590-C-G is Benign according to our data. Variant chr1-216323590-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48437.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1920/152048) while in subpopulation NFE AF = 0.0187 (1270/67972). AF 95% confidence interval is 0.0178. There are 18 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.1434G>C	p.Glu478Asp	missense	Exon 8 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.1434G>C	p.Glu478Asp	missense	Exon 8 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 151932 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0121 AC: 3034 AN: 250826 AF XY: 0.0119

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00811

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0165 AC: 24111 AN: 1461464 Hom.: 235 Cov.: 30 AF XY: 0.0163 AC XY: 11829 AN XY: 727034

African (AFR) AF: 0.00293 AC: 98 AN: 33454

American (AMR) AF: 0.00882 AC: 394 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86250

European-Finnish (FIN) AF: 0.0165 AC: 883 AN: 53418

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.0190 AC: 21163 AN: 1111776

Other (OTH) AF: 0.0143 AC: 863 AN: 60370

GnomAD4 genome AF: 0.0126 AC: 1920 AN: 152048 Hom.: 18 Cov.: 31 AF XY: 0.0124 AC XY: 921 AN XY: 74270

African (AFR) AF: 0.00352 AC: 146 AN: 41508

American (AMR) AF: 0.0114 AC: 174 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.0151 AC: 159 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1270 AN: 67972

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0174 Hom.: 21

Bravo AF: 0.0124

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0157 AC: 135

ExAC AF: 0.0118 AC: 1437

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0179

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Usher syndrome type 2A (3)
-	-	2	Retinal dystrophy (2)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.043
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.044
Sift	Benign	0.15	T
Sift4G	Uncertain	0.037	D
Polyphen		0.10	B
Vest4		0.076
MutPred		0.65		Loss of ubiquitination at K481 (P = 0.1778)
MPC		0.12
ClinPred		0.016	T
GERP RS		0.84
Varity_R		0.13
gMVP		0.44
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35730265; hg19: chr1-216496932; COSMIC: COSV99048308;