rs142481947

Variant names:

• chr1-215743258-C-T
• rs142481947
• NM_206933.4:c.11467G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_206933.4(USH2A):​c.11467G>A​(p.Val3823Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,611,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3823A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 2.60
• 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 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015349627).
• BP6: Variant 1-215743258-C-T is Benign according to our data. Variant chr1-215743258-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281728.

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.11467G>A	p.Val3823Ile	missense	Exon 59 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.11467G>A	p.Val3823Ile	missense	Exon 59 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.11467G>A	p.Val3823Ile	missense	Exon 59 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 166 AN: 150338 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.000302 AC: 76 AN: 251424 AF XY: 0.000213

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1461196 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 726928

African (AFR) AF: 0.00329 AC: 110 AN: 33468

American (AMR) AF: 0.000224 AC: 10 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39630

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111584

Other (OTH) AF: 0.000182 AC: 11 AN: 60358

GnomAD4 genome AF: 0.00111 AC: 167 AN: 150458 Hom.: 0 Cov.: 26 AF XY: 0.000926 AC XY: 68 AN XY: 73404

African (AFR) AF: 0.00383 AC: 157 AN: 40974

American (AMR) AF: 0.000335 AC: 5 AN: 14938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10242

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67702

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.00119

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)
-	-	1	USH2A-related disorder (1)
-	1	-	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.89
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Uncertain	0.026	D
Sift4G	Benign	0.088	T
Polyphen		0.021	B
Vest4		0.088
MVP		0.64
MPC		0.031
ClinPred		0.020	T
GERP RS		2.9
Varity_R		0.089
gMVP		0.19
Mutation Taster		=89/11	polymorphism

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: rs142481947; hg19: chr1-215916600; COSMIC: COSV56323012;