rs11120645

Variant names:

• chr1-215817137-C-T
• rs11120645
• NM_206933.4:c.9430G>A
• USH2A p.Asp3144Asn

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.9430G>A​(p.Asp3144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,664 control chromosomes in the GnomAD database, including 773 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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 0.034 (96 hom., cov: 32)
  • Exomes 𝑓: 0.028 (677 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.34
• Publications: 10 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061059594).
• BP6: Variant 1-215817137-C-T is Benign according to our data. Variant chr1-215817137-C-T is described in ClinVar as Benign. ClinVar VariationId is 48627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 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.9430G>A	p.Asp3144Asn	missense	Exon 48 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.9430G>A	p.Asp3144Asn	missense	Exon 48 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.9430G>A	p.Asp3144Asn	missense	Exon 48 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5133 AN: 151854 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0446

GnomAD2 exomes AF: 0.0260 AC: 6499 AN: 250212 AF XY: 0.0257

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0284 AC: 41486 AN: 1460694 Hom.: 677 Cov.: 30 AF XY: 0.0279 AC XY: 20263 AN XY: 726656

African (AFR) AF: 0.0527 AC: 1761 AN: 33424

American (AMR) AF: 0.0263 AC: 1174 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 1037 AN: 26080

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39672

South Asian (SAS) AF: 0.00348 AC: 300 AN: 86240

European-Finnish (FIN) AF: 0.0274 AC: 1465 AN: 53410

Middle Eastern (MID) AF: 0.0378 AC: 218 AN: 5760

European-Non Finnish (NFE) AF: 0.0303 AC: 33629 AN: 1111096

Other (OTH) AF: 0.0315 AC: 1898 AN: 60328

GnomAD4 genome AF: 0.0339 AC: 5146 AN: 151970 Hom.: 96 Cov.: 32 AF XY: 0.0336 AC XY: 2494 AN XY: 74256

African (AFR) AF: 0.0501 AC: 2078 AN: 41516

American (AMR) AF: 0.0359 AC: 545 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3464

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.0258 AC: 273 AN: 10592

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0287 AC: 1948 AN: 67918

Other (OTH) AF: 0.0446 AC: 94 AN: 2106

Alfa AF: 0.0301 Hom.: 264

Bravo AF: 0.0376

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0297

EpiControl AF: 0.0352

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 2A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Varity_R		0.15
gMVP		0.35
Mutation Taster		=88/12	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11120645;

hg19: chr1-215990479;

COSMIC: COSV56389684;