1-216125293-T-C

Variant names:

• chr1-216125293-T-C
• rs532342
• NM_206933.4:c.4628-28080A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_206933.4(USH2A):​c.4628-28080A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 151,816 control chromosomes in the GnomAD database, including 47,302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (47302 hom., cov: 30)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.4628-28080A>G		intron	N/A	NP_996816.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4628-28080A>G		intron	N/A	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.4628-28080A>G		intron	N/A	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.783 AC: 118739 AN: 151702 Hom.: 47303 Cov.: 30

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.783

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.782 AC: 118776 AN: 151816 Hom.: 47302 Cov.: 30 AF XY: 0.788 AC XY: 58410 AN XY: 74170

African (AFR) AF: 0.629 AC: 26015 AN: 41386

American (AMR) AF: 0.843 AC: 12863 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2684 AN: 3470

East Asian (EAS) AF: 0.980 AC: 5041 AN: 5146

South Asian (SAS) AF: 0.886 AC: 4269 AN: 4816

European-Finnish (FIN) AF: 0.846 AC: 8871 AN: 10486

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.831 AC: 56444 AN: 67940

Other (OTH) AF: 0.781 AC: 1645 AN: 2106

Alfa AF: 0.815 Hom.: 94464

Bravo AF: 0.775

Asia WGS AF: 0.858 AC: 2984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.73
DANN	Benign	0.29
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs532342; hg19: chr1-216298635;