rs2797234

Variant names:

• chr1-215675245-T-C
• rs2797234
• NM_206933.4:c.12666A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.12666A>G​(p.Thr4222Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,613,974 control chromosomes in the GnomAD database, including 114,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.34 (9403 hom., cov: 33)
  • Exomes 𝑓: 0.38 (104936 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.426
• Publications: 25 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 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-215675245-T-C is Benign according to our data. Variant chr1-215675245-T-C is described in ClinVar as Benign. ClinVar VariationId is 48403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 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.12666A>G	p.Thr4222Thr	synonymous	Exon 63 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.12666A>G	p.Thr4222Thr	synonymous	Exon 63 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.12666A>G	p.Thr4222Thr	synonymous	Exon 63 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51541 AN: 152062 Hom.: 9406 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.370 AC: 92457 AN: 250022 AF XY: 0.368

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.375 AC: 548818 AN: 1461794 Hom.: 104936 Cov.: 74 AF XY: 0.374 AC XY: 271649 AN XY: 727198

African (AFR) AF: 0.211 AC: 7079 AN: 33478

American (AMR) AF: 0.462 AC: 20654 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8192 AN: 26136

East Asian (EAS) AF: 0.255 AC: 10108 AN: 39694

South Asian (SAS) AF: 0.307 AC: 26487 AN: 86256

European-Finnish (FIN) AF: 0.399 AC: 21322 AN: 53396

Middle Eastern (MID) AF: 0.333 AC: 1923 AN: 5768

European-Non Finnish (NFE) AF: 0.388 AC: 431301 AN: 1111958

Other (OTH) AF: 0.360 AC: 21752 AN: 60390

GnomAD4 genome AF: 0.339 AC: 51546 AN: 152180 Hom.: 9403 Cov.: 33 AF XY: 0.339 AC XY: 25210 AN XY: 74380

African (AFR) AF: 0.219 AC: 9109 AN: 41530

American (AMR) AF: 0.416 AC: 6368 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3472

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5162

South Asian (SAS) AF: 0.297 AC: 1435 AN: 4824

European-Finnish (FIN) AF: 0.402 AC: 4253 AN: 10578

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26565 AN: 68010

Other (OTH) AF: 0.333 AC: 702 AN: 2110

Alfa AF: 0.367 Hom.: 30830

Bravo AF: 0.335

Asia WGS AF: 0.275 AC: 953 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.374

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.33
DANN	Benign	0.40
PhyloP100		-0.43
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: rs2797234; hg19: chr1-215848587; COSMIC: COSV56342646;