rs3767698

Variant names:

• chr1-216325569-A-C
• rs3767698
• NM_206933.4:c.879T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_206933.4(USH2A):​c.879T>G​(p.Leu293Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,342 control chromosomes in the GnomAD database, including 121 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 0.0028 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (107 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.892
• Publications: 12 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-216325569-A-C is Benign according to our data. Variant chr1-216325569-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48609.
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

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.879T>G	p.Leu293Leu	synonymous	Exon 6 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.879T>G	p.Leu293Leu	synonymous	Exon 6 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.879T>G	p.Leu293Leu	synonymous	Exon 6 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.879T>G	p.Leu293Leu	synonymous	Exon 6 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.879T>G	p.Leu293Leu	synonymous	Exon 6 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152040 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00555 AC: 1387 AN: 249974 AF XY: 0.00497

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00691

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.0582

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00233 AC: 3400 AN: 1461184 Hom.: 107 Cov.: 31 AF XY: 0.00231 AC XY: 1676 AN XY: 726912

African (AFR) AF: 0.000209 AC: 7 AN: 33452

American (AMR) AF: 0.00647 AC: 289 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26118

East Asian (EAS) AF: 0.0675 AC: 2672 AN: 39612

South Asian (SAS) AF: 0.00253 AC: 218 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111624

Other (OTH) AF: 0.00263 AC: 159 AN: 60350

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152158 Hom.: 14 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74372

African (AFR) AF: 0.000434 AC: 18 AN: 41518

American (AMR) AF: 0.00288 AC: 44 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.0647 AC: 333 AN: 5144

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000592 Hom.: 1

Bravo AF: 0.00340

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		-0.89
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3767698; hg19: chr1-216498911;