rs56222536

Variant names:

• chr1-216084871-A-G
• rs56222536
• NM_206933.4:c.4994T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-216084871-A-G
• chr1-216084871-A-T

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.4994T>C​(p.Ile1665Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,682 control chromosomes in the GnomAD database, including 14,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.10 (1044 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13535 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.681
• Publications: 20 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014926493).
• BP6: Variant 1-216084871-A-G is Benign according to our data. Variant chr1-216084871-A-G is described in ClinVar as Benign. ClinVar VariationId is 48525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 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.4994T>C	p.Ile1665Thr	missense	Exon 25 of 72	NP_996816.3	O75445-1
	USH2A-AS2	NR_125992.1		n.266-1851A>G		intron	N/A
	USH2A-AS2	NR_125993.1		n.137-1851A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4994T>C	p.Ile1665Thr	missense	Exon 25 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.4994T>C	p.Ile1665Thr	missense	Exon 25 of 73	ENSP00000501296.1	O75445-3
	USH2A	ENST00000463147.1	TSL:2	n.238T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15330 AN: 152112 Hom.: 1044 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.0705

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.110 AC: 27645 AN: 250302 AF XY: 0.113

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.0209

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 191566 AN: 1460452 Hom.: 13535 Cov.: 32 AF XY: 0.130 AC XY: 94740 AN XY: 726616

African (AFR) AF: 0.0215 AC: 718 AN: 33412

American (AMR) AF: 0.0891 AC: 3972 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4766 AN: 26096

East Asian (EAS) AF: 0.0213 AC: 844 AN: 39672

South Asian (SAS) AF: 0.0744 AC: 6414 AN: 86238

European-Finnish (FIN) AF: 0.132 AC: 7047 AN: 53304

Middle Eastern (MID) AF: 0.168 AC: 966 AN: 5754

European-Non Finnish (NFE) AF: 0.143 AC: 158971 AN: 1111068

Other (OTH) AF: 0.130 AC: 7868 AN: 60312

GnomAD4 genome AF: 0.101 AC: 15331 AN: 152230 Hom.: 1044 Cov.: 32 AF XY: 0.101 AC XY: 7482 AN XY: 74420

African (AFR) AF: 0.0256 AC: 1063 AN: 41566

American (AMR) AF: 0.108 AC: 1657 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3470

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5180

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4830

European-Finnish (FIN) AF: 0.131 AC: 1383 AN: 10594

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9591 AN: 67982

Other (OTH) AF: 0.129 AC: 272 AN: 2116

Alfa AF: 0.135 Hom.: 2643

Bravo AF: 0.0974

TwinsUK AF: 0.136 AC: 504

ALSPAC AF: 0.144 AC: 554

ESP6500AA AF: 0.0282 AC: 124

ESP6500EA AF: 0.157 AC: 1354

ExAC AF: 0.110 AC: 13301

Asia WGS AF: 0.0610 AC: 212 AN: 3476

EpiCase AF: 0.153

EpiControl AF: 0.152

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.92
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.68
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Uncertain	0.041	D
Polyphen		0.0070	B
Vest4		0.075
MPC		0.035
ClinPred		0.0013	T
GERP RS		2.6
Varity_R		0.089
gMVP		0.40
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56222536; hg19: chr1-216258213; COSMIC: COSV56370415;