rs114194722

Variant names:

• chr1-216418694-G-A
• rs114194722
• NM_206933.4:c.486-15C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_206933.4(USH2A):​c.486-15C>T variant causes a intron change. The variant allele was found at a frequency of 0.00256 in 1,612,444 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (5 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 3.92
• 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 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

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 1-216418694-G-A is Benign according to our data. Variant chr1-216418694-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 295447.
• BS2: High Homozygotes in GnomAdExome4 at 5 Unknown,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.486-15C>T		intron	N/A	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.486-15C>T		intron	N/A	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.486-15C>T		intron	N/A	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.486-15C>T		intron	N/A	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.486-15C>T		intron	N/A	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 151944 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00130 AC: 326 AN: 250392 AF XY: 0.00126

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00268 AC: 3911 AN: 1460382 Hom.: 5 Cov.: 33 AF XY: 0.00250 AC XY: 1817 AN XY: 726510

African (AFR) AF: 0.000509 AC: 17 AN: 33394

American (AMR) AF: 0.000426 AC: 19 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53310

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00334 AC: 3709 AN: 1111060

Other (OTH) AF: 0.00249 AC: 150 AN: 60306

GnomAD4 genome AF: 0.00143 AC: 217 AN: 152062 Hom.: 1 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74340

African (AFR) AF: 0.000433 AC: 18 AN: 41526

American (AMR) AF: 0.00118 AC: 18 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 67976

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00143

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Usher syndrome type 2A (2)
-	-	1	not specified (1)
-	1	-	Retinitis pigmentosa (1)
-	-	1	USH2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.78
PhyloP100		3.9
Mutation Taster		=99/1	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: rs114194722; hg19: chr1-216592036;