1-216175319-G-A

Variant names:

• chr1-216175319-G-A
• rs148000219
• NM_206933.4:c.4560C>T

Variant summary

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

The NM_206933.4(USH2A):​c.4560C>T​(p.Ile1520Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,613,778 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. I1520I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: 0.0920
• Publications: 4 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=-0.79).
• BP6: Variant 1-216175319-G-A is Benign according to our data. Variant chr1-216175319-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48518.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.4560C>T	p.Ile1520Ile	synonymous	Exon 21 of 72	NP_996816.3
	USH2A	NM_007123.6		c.4560C>T	p.Ile1520Ile	synonymous	Exon 21 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.4560C>T	p.Ile1520Ile	synonymous	Exon 21 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.4560C>T	p.Ile1520Ile	synonymous	Exon 21 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.4560C>T	p.Ile1520Ile	synonymous	Exon 21 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00250 AC: 626 AN: 250572 AF XY: 0.00249

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000971

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00351 AC: 5129 AN: 1461518 Hom.: 11 Cov.: 32 AF XY: 0.00347 AC XY: 2521 AN XY: 727054

African (AFR) AF: 0.000508 AC: 17 AN: 33472

American (AMR) AF: 0.00224 AC: 100 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86256

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53390

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.00398 AC: 4424 AN: 1111838

Other (OTH) AF: 0.00373 AC: 225 AN: 60372

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74438

African (AFR) AF: 0.000722 AC: 30 AN: 41558

American (AMR) AF: 0.00249 AC: 38 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.00220

EpiCase AF: 0.00333

EpiControl AF: 0.00338

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	1	2	Usher syndrome type 2A (3)
-	-	2	not specified (2)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.88
DANN	Benign	0.58
PhyloP100		0.092
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs148000219; hg19: chr1-216348661; COSMIC: COSV56424773;