1-215883006-A-G

Variant names:

• chr1-215883006-A-G
• rs17025548
• NM_206933.4:c.8224-3908T>C

Variant summary

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

The NM_206933.4(USH2A):​c.8224-3908T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,136 control chromosomes in the GnomAD database, including 1,765 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 0.15 (1765 hom., cov: 33)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• Publications: 2 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.8224-3908T>C		intron_variant	Intron 41 of 71	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.8224-3908T>C		intron_variant	Intron 41 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.8224-3908T>C		intron_variant	Intron 41 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22741 AN: 152018 Hom.: 1759 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.152

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

GnomAD4 genome AF: 0.150 AC: 22753 AN: 152136 Hom.: 1765 Cov.: 33 AF XY: 0.151 AC XY: 11213 AN XY: 74374

African (AFR) AF: 0.162 AC: 6707 AN: 41524

American (AMR) AF: 0.108 AC: 1647 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3470

East Asian (EAS) AF: 0.242 AC: 1251 AN: 5176

South Asian (SAS) AF: 0.254 AC: 1225 AN: 4826

European-Finnish (FIN) AF: 0.135 AC: 1425 AN: 10594

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.142 AC: 9676 AN: 67940

Other (OTH) AF: 0.153 AC: 324 AN: 2114

Alfa AF: 0.146 Hom.: 984

Bravo AF: 0.147

Asia WGS AF: 0.246 AC: 849 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		0.63
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: rs17025548; hg19: chr1-216056348; COSMIC: COSV56432600; COSMIC: COSV56432600;