rs200940197

Variant names:

• chr1-216323494-G-A
• rs200940197
• NM_206933.4:c.1530C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000307340.8(USH2A):​c.1530C>T​(p.Asp510Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,613,196 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (9 hom.)
• Consequence: USH2A ENST00000307340.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.480
• Publications: 0 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 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-216323494-G-A is Benign according to our data. Variant chr1-216323494-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178992.
• BP7: Synonymous conserved (PhyloP=0.48 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307340.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.1530C>T	p.Asp510Asp	synonymous	Exon 8 of 72	NP_996816.3
	USH2A	NM_007123.6		c.1530C>T	p.Asp510Asp	synonymous	Exon 8 of 21	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.1530C>T	p.Asp510Asp	synonymous	Exon 8 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.1530C>T	p.Asp510Asp	synonymous	Exon 8 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.1530C>T	p.Asp510Asp	synonymous	Exon 8 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151792 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000897 AC: 225 AN: 250760 AF XY: 0.00130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000509 AC: 744 AN: 1461292 Hom.: 9 Cov.: 30 AF XY: 0.000736 AC XY: 535 AN XY: 726956

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.0000671 AC: 3 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39632

South Asian (SAS) AF: 0.00771 AC: 665 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111654

Other (OTH) AF: 0.000762 AC: 46 AN: 60360

GnomAD4 genome AF: 0.000316 AC: 48 AN: 151904 Hom.: 1 Cov.: 31 AF XY: 0.000472 AC XY: 35 AN XY: 74216

African (AFR) AF: 0.0000723 AC: 3 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00852 AC: 41 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000793 Hom.: 0

Bravo AF: 0.000106

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		0.48
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200940197; hg19: chr1-216496836;