1-216378749-C-T

Variant names:

• chr1-216378749-C-T
• rs2669053
• NM_206933.4:c.652-13664G>A

Variant summary

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

The NM_206933.4(USH2A):​c.652-13664G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,834 control chromosomes in the GnomAD database, including 26,675 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 0.58 (26675 hom., cov: 31)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.652-13664G>A		intron	N/A	NP_996816.3
	USH2A	NM_007123.6		c.652-13664G>A		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.652-13664G>A		intron	N/A	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.652-13664G>A		intron	N/A	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.652-13664G>A		intron	N/A	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87578 AN: 151716 Hom.: 26657 Cov.: 31

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.588

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

GnomAD4 genome AF: 0.577 AC: 87623 AN: 151834 Hom.: 26675 Cov.: 31 AF XY: 0.582 AC XY: 43213 AN XY: 74192

African (AFR) AF: 0.368 AC: 15210 AN: 41386

American (AMR) AF: 0.634 AC: 9667 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2024 AN: 3470

East Asian (EAS) AF: 0.803 AC: 4137 AN: 5152

South Asian (SAS) AF: 0.624 AC: 3003 AN: 4810

European-Finnish (FIN) AF: 0.704 AC: 7417 AN: 10536

Middle Eastern (MID) AF: 0.455 AC: 132 AN: 290

European-Non Finnish (NFE) AF: 0.650 AC: 44143 AN: 67936

Other (OTH) AF: 0.588 AC: 1239 AN: 2108

Alfa AF: 0.625 Hom.: 104601

Bravo AF: 0.564

Asia WGS AF: 0.661 AC: 2297 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.61
PhyloP100		0.18
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: rs2669053; hg19: chr1-216552091;