rs727503735

Variant names:

• chr1-216217405-G-C
• rs727503735
• NM_206933.4:c.3139C>G

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.3139C>G​(p.Leu1047Val) variant causes a missense change. The variant allele was found at a frequency of 0.000098 in 1,612,940 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Synonymous variant affecting the same amino acid position (i.e. L1047L) has been classified as Likely benign. The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.37
• Publications: 4 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

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018493354).
• BP6: Variant 1-216217405-G-C is Benign according to our data. Variant chr1-216217405-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166512.

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.3139C>G	p.Leu1047Val	missense	Exon 15 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.3139C>G	p.Leu1047Val	missense	Exon 15 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.3139C>G	p.Leu1047Val	missense	Exon 15 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.3139C>G	p.Leu1047Val	missense	Exon 15 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.3139C>G	p.Leu1047Val	missense	Exon 15 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000216 AC: 54 AN: 250414 AF XY: 0.000200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.0000986 AC: 144 AN: 1460880 Hom.: 1 Cov.: 33 AF XY: 0.0000949 AC XY: 69 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.000134 AC: 6 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111350

Other (OTH) AF: 0.000265 AC: 16 AN: 60350

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

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

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.089
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.55	P
Vest4		0.26
MutPred		0.43		Gain of disorder (P = 0.2296)
MVP		0.83
MPC		0.078
ClinPred		0.084	T
GERP RS		3.3
Varity_R		0.076
gMVP		0.23
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs727503735; hg19: chr1-216390747;