rs10779261

Variant names:

• chr1-216421964-C-T
• rs10779261
• NM_206933.4:c.373G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-216421964-C-T
• chr1-216421964-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.373G>A​(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,698 control chromosomes in the GnomAD database, including 418,913 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40885 hom., cov: 32)
  • Exomes 𝑓: 0.72 (378028 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.358
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3263331E-6).
• BP6: Variant 1-216421964-C-T is Benign according to our data. Variant chr1-216421964-C-T is described in ClinVar as Benign. ClinVar VariationId is 48507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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.373G>A	p.Ala125Thr	missense	Exon 2 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.373G>A	p.Ala125Thr	missense	Exon 2 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.373G>A	p.Ala125Thr	missense	Exon 2 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.373G>A	p.Ala125Thr	missense	Exon 2 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.373G>A	p.Ala125Thr	missense	Exon 2 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111235 AN: 151902 Hom.: 40838 Cov.: 32

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.695

GnomAD2 exomes AF: 0.729 AC: 182834 AN: 250924 AF XY: 0.725

Gnomad AFR exome AF: 0.757

Gnomad AMR exome AF: 0.730

Gnomad ASJ exome AF: 0.658

Gnomad EAS exome AF: 0.836

Gnomad FIN exome AF: 0.774

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.718 AC: 1049721 AN: 1461678 Hom.: 378028 Cov.: 86 AF XY: 0.717 AC XY: 521325 AN XY: 727130

African (AFR) AF: 0.757 AC: 25343 AN: 33470

American (AMR) AF: 0.731 AC: 32673 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17085 AN: 26128

East Asian (EAS) AF: 0.845 AC: 33561 AN: 39694

South Asian (SAS) AF: 0.728 AC: 62821 AN: 86256

European-Finnish (FIN) AF: 0.768 AC: 41027 AN: 53406

Middle Eastern (MID) AF: 0.648 AC: 3735 AN: 5766

European-Non Finnish (NFE) AF: 0.711 AC: 790289 AN: 1111896

Other (OTH) AF: 0.715 AC: 43187 AN: 60380

GnomAD4 genome AF: 0.732 AC: 111334 AN: 152020 Hom.: 40885 Cov.: 32 AF XY: 0.737 AC XY: 54765 AN XY: 74290

African (AFR) AF: 0.756 AC: 31324 AN: 41454

American (AMR) AF: 0.723 AC: 11024 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2278 AN: 3466

East Asian (EAS) AF: 0.833 AC: 4296 AN: 5158

South Asian (SAS) AF: 0.760 AC: 3668 AN: 4824

European-Finnish (FIN) AF: 0.779 AC: 8223 AN: 10560

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 48151 AN: 67986

Other (OTH) AF: 0.697 AC: 1473 AN: 2112

Alfa AF: 0.711 Hom.: 188724

Bravo AF: 0.727

TwinsUK AF: 0.718 AC: 2661

ALSPAC AF: 0.710 AC: 2736

ESP6500AA AF: 0.758 AC: 3339

ESP6500EA AF: 0.699 AC: 6012

ExAC AF: 0.729 AC: 88518

Asia WGS AF: 0.788 AC: 2742 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Usher syndrome type 2A (4)
-	-	3	not provided (3)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.30
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.36
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0030
MPC		0.030
ClinPred		0.0021	T
GERP RS		-1.4
Varity_R		0.041
gMVP		0.24
Mutation Taster		=99/1	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: rs10779261; hg19: chr1-216595306; COSMIC: COSV107316657;