rs41308435

Variant names:

• chr1-215634680-T-C
• rs41308435
• NM_206933.4:c.15076A>G

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.15076A>G​(p.Lys5026Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 1,614,214 control chromosomes in the GnomAD database, including 367 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0061 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (343 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.72
• Publications: 17 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 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.0022268891).
• BP6: Variant 1-215634680-T-C is Benign according to our data. Variant chr1-215634680-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0649 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.15076A>G	p.Lys5026Glu	missense	Exon 70 of 72	NP_996816.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.15076A>G	p.Lys5026Glu	missense	Exon 70 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.15076A>G	p.Lys5026Glu	missense	Exon 70 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152218 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0125 AC: 3137 AN: 251416 AF XY: 0.0155

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00916 AC: 13384 AN: 1461878 Hom.: 343 Cov.: 32 AF XY: 0.0108 AC XY: 7848 AN XY: 727240

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0493 AC: 1958 AN: 39700

South Asian (SAS) AF: 0.0680 AC: 5866 AN: 86258

European-Finnish (FIN) AF: 0.00253 AC: 135 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.00425 AC: 4721 AN: 1111998

Other (OTH) AF: 0.00916 AC: 553 AN: 60396

GnomAD4 genome AF: 0.00609 AC: 928 AN: 152336 Hom.: 24 Cov.: 32 AF XY: 0.00749 AC XY: 558 AN XY: 74478

African (AFR) AF: 0.00113 AC: 47 AN: 41576

American (AMR) AF: 0.00601 AC: 92 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5190

South Asian (SAS) AF: 0.0711 AC: 343 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00342 AC: 233 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00464 Hom.: 18

Bravo AF: 0.00437

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.0134 AC: 1626

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00308

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.49
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.7
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.062
MPC		0.036
ClinPred		0.00052	T
GERP RS		3.9
Varity_R		0.067
gMVP		0.13
Mutation Taster		=99/1	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: rs41308435; hg19: chr1-215808022;