rs1805049

Variant names:

• chr1-216175422-C-T
• rs1805049
• NM_206933.4:c.4457G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-216175422-C-T
• chr1-216175422-C-A
• chr1-216175422-C-G

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.4457G>A​(p.Arg1486Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,420 control chromosomes in the GnomAD database, including 326,396 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30324 hom., cov: 32)
  • Exomes 𝑓: 0.63 (296072 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.52
• Publications: 55 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

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, 3 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=1.6309556E-6).
• BP6: Variant 1-216175422-C-T is Benign according to our data. Variant chr1-216175422-C-T is described in ClinVar as Benign. ClinVar VariationId is 177992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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.4457G>A	p.Arg1486Lys	missense	Exon 21 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.4457G>A	p.Arg1486Lys	missense	Exon 21 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4457G>A	p.Arg1486Lys	missense	Exon 21 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.4457G>A	p.Arg1486Lys	missense	Exon 21 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.4457G>A	p.Arg1486Lys	missense	Exon 21 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95572 AN: 151932 Hom.: 30303 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.661 AC: 165406 AN: 250414 AF XY: 0.659

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.781

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.635 AC: 927401 AN: 1461370 Hom.: 296072 Cov.: 71 AF XY: 0.635 AC XY: 461871 AN XY: 726974

African (AFR) AF: 0.574 AC: 19199 AN: 33470

American (AMR) AF: 0.710 AC: 31736 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 15019 AN: 26120

East Asian (EAS) AF: 0.799 AC: 31656 AN: 39620

South Asian (SAS) AF: 0.698 AC: 60164 AN: 86256

European-Finnish (FIN) AF: 0.712 AC: 38022 AN: 53386

Middle Eastern (MID) AF: 0.606 AC: 3491 AN: 5756

European-Non Finnish (NFE) AF: 0.621 AC: 689907 AN: 1111728

Other (OTH) AF: 0.633 AC: 38207 AN: 60358

GnomAD4 genome AF: 0.629 AC: 95627 AN: 152050 Hom.: 30324 Cov.: 32 AF XY: 0.636 AC XY: 47233 AN XY: 74316

African (AFR) AF: 0.576 AC: 23911 AN: 41482

American (AMR) AF: 0.662 AC: 10103 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2038 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3918 AN: 5140

South Asian (SAS) AF: 0.710 AC: 3421 AN: 4820

European-Finnish (FIN) AF: 0.728 AC: 7699 AN: 10576

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42324 AN: 67984

Other (OTH) AF: 0.627 AC: 1319 AN: 2104

Alfa AF: 0.624 Hom.: 119883

Bravo AF: 0.624

TwinsUK AF: 0.621 AC: 2302

ALSPAC AF: 0.625 AC: 2408

ESP6500AA AF: 0.596 AC: 2626

ESP6500EA AF: 0.612 AC: 5261

ExAC AF: 0.657 AC: 79731

Asia WGS AF: 0.731 AC: 2543 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.8
DANN	Benign	0.90
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.024
Sift	Benign	0.42	T
Sift4G	Benign	0.37	T
Polyphen		0.094	B
Vest4		0.044
MPC		0.032
ClinPred		0.0025	T
GERP RS		-2.2
Varity_R		0.085
gMVP		0.34
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1805049; hg19: chr1-216348764; COSMIC: COSV56346078;