rs696723

Variant names:

• chr1-216250933-C-G
• rs696723
• NM_206933.4:c.2137G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-216250933-C-G
• chr1-216250933-C-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.2137G>C​(p.Gly713Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0202 in 1,613,916 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G713G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.058 (655 hom., cov: 32)
  • Exomes 𝑓: 0.016 (779 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 5.51
• Publications: 30 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 0 benign, 7 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021301508).
• BP6: Variant 1-216250933-C-G is Benign according to our data. Variant chr1-216250933-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 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.2137G>C	p.Gly713Arg	missense	Exon 12 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.2137G>C	p.Gly713Arg	missense	Exon 12 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.2137G>C	p.Gly713Arg	missense	Exon 12 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.2137G>C	p.Gly713Arg	missense	Exon 12 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.2137G>C	p.Gly713Arg	missense	Exon 12 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8754 AN: 152066 Hom.: 654 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0444

GnomAD2 exomes AF: 0.0232 AC: 5814 AN: 250936 AF XY: 0.0207

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00689

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0163 AC: 23891 AN: 1461732 Hom.: 779 Cov.: 32 AF XY: 0.0159 AC XY: 11536 AN XY: 727172

African (AFR) AF: 0.185 AC: 6196 AN: 33480

American (AMR) AF: 0.0162 AC: 724 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 466 AN: 26128

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39640

South Asian (SAS) AF: 0.0209 AC: 1802 AN: 86256

European-Finnish (FIN) AF: 0.00618 AC: 330 AN: 53408

Middle Eastern (MID) AF: 0.0293 AC: 169 AN: 5766

European-Non Finnish (NFE) AF: 0.0115 AC: 12793 AN: 1111944

Other (OTH) AF: 0.0233 AC: 1409 AN: 60390

GnomAD4 genome AF: 0.0576 AC: 8765 AN: 152184 Hom.: 655 Cov.: 32 AF XY: 0.0563 AC XY: 4186 AN XY: 74408

African (AFR) AF: 0.176 AC: 7301 AN: 41476

American (AMR) AF: 0.0277 AC: 423 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4824

European-Finnish (FIN) AF: 0.00632 AC: 67 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 716 AN: 68018

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0186 Hom.: 86

Bravo AF: 0.0655

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.174 AC: 768

ESP6500EA AF: 0.0113 AC: 97

ExAC AF: 0.0256 AC: 3104

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0129

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	4	not specified (4)
-	-	4	Usher syndrome type 2A (4)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.34
MPC		0.25
ClinPred		0.057	T
GERP RS		4.2
Varity_R		0.84
gMVP		0.91
Mutation Taster		=65/35	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: rs696723; hg19: chr1-216424275; COSMIC: COSV56363761;