rs727504652

Variant names:

• chr1-216199854-C-A
• rs727504652
• NM_206933.4:c.3584G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216199854-C-A
• chr1-216199854-C-G
• chr1-216199854-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_206933.4(USH2A):​c.3584G>T​(p.Cys1195Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1195S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 1.74
• Publications: 3 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.3584G>T	p.Cys1195Phe	missense	Exon 17 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.3584G>T	p.Cys1195Phe	missense	Exon 17 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.3584G>T	p.Cys1195Phe	missense	Exon 17 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.3584G>T	p.Cys1195Phe	missense	Exon 17 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.3584G>T	p.Cys1195Phe	missense	Exon 17 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Usher syndrome type 2A (3)
-	2	-	not provided (2)
-	2	-	Retinal dystrophy (2)
-	2	-	Retinitis pigmentosa 39 (2)
-	1	-	not specified (1)
-	1	-	Retinitis pigmentosa (1)
-	1	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.7
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.27
Sift	Benign	0.20	T
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.40		Loss of catalytic residue at P1194 (P = 0.0079)
MVP		0.93
MPC		0.042
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.64
gMVP		0.62
Mutation Taster		=2/98	disease causing

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: rs727504652; hg19: chr1-216373196;