1-216418692-C-T

Position:

• chr1-216418692-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_206933.4(USH2A):​c.486-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,612,572 control chromosomes in the GnomAD database, including 8 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 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.300

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-216418692-C-T is Benign according to our data. Variant chr1-216418692-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166531.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr1-216418692-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.486-13G>A		intron_variant		ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.486-13G>A		intron_variant			NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.486-13G>A		intron_variant		1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.486-13G>A		intron_variant		1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.486-13G>A		intron_variant				ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 553 AN: 151922 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000906 AC: 227 AN: 250474 Hom.: 0 AF XY: 0.000687 AC XY: 93 AN XY: 135368

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000344 AC: 502 AN: 1460532 Hom.: 4 Cov.: 33 AF XY: 0.000271 AC XY: 197 AN XY: 726580

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152040 Hom.: 4 Cov.: 32 AF XY: 0.00353 AC XY: 262 AN XY: 74286

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.000984

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00383

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

486-13G>A in Intron 02 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.8% (31/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs116367260). -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.69

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: rs116367260; hg19: chr1-216592034;