rs150209313

chr1-216327668-CAT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):c.785-16_785-15del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,612,814 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: USH2A NM_206933.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.191

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-216327668-CAT-C is Benign according to our data. Variant chr1-216327668-CAT-C is described in ClinVar as [Benign]. Clinvar id is 227147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216327668-CAT-C is described in Lovd as [Benign]. Variant chr1-216327668-CAT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000808 (123/152238) while in subpopulation EAS AF= 0.0209 (108/5174). AF 95% confidence interval is 0.0177. There are 2 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.785-16_785-15del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000307340.8
USH2A	NM_007123.6	c.785-16_785-15del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.785-16_785-15del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.785-16_785-15del		splice_polypyrimidine_tract_variant, intron_variant		1
USH2A	ENST00000674083.1	c.785-16_785-15del		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152120 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00131 AC: 329 AN: 250668 Hom.: 3 AF XY: 0.00123 AC XY: 167 AN XY: 135484

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0163

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000505 AC: 738 AN: 1460576 Hom.: 6 AF XY: 0.000519 AC XY: 377 AN XY: 726604

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152238 Hom.: 2 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74432

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.0120 AC: 43 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 05, 2015

c.785-16_785-15delAT in intron 4 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.6% (134/8536) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs150209313). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs150209313; hg19: chr1-216501010;