rs146916397

chr1-216246617-C-Achr1-216246617-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_206933.4(USH2A):c.2777G>T(p.Arg926Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R926C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.693

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 9) in uniprot entity USH2A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-216246618-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.2777G>T	p.Arg926Leu	missense_variant	13/72	ENST00000307340.8
USH2A	NM_007123.6	c.2777G>T	p.Arg926Leu	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.2777G>T	p.Arg926Leu	missense_variant	13/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.2777G>T	p.Arg926Leu	missense_variant	13/21	1
USH2A	ENST00000674083.1	c.2777G>T	p.Arg926Leu	missense_variant	13/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.53	D;D;D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;T
Sift4G	Uncertain	0.0090	D;T
Polyphen		0.96	D;P
Vest4		0.69
MutPred		0.51		Loss of disorder (P = 0.0516);Loss of disorder (P = 0.0516);
MVP		0.82
MPC		0.22
ClinPred		0.96	D
GERP RS		2.7
Varity_R		0.37
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146916397; hg19: chr1-216419959;