rs1553274535

Positions:

• chr1-215900864-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000307340.8(USH2A):​c.7342C>G​(p.Pro2448Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P2448P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH2A ENST00000307340.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7342C>G	p.Pro2448Ala	missense_variant	39/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7342C>G	p.Pro2448Ala	missense_variant	39/72	1	NM_206933.4	ENSP00000305941	P1
	ENST00000414995.1	n.200G>C		non_coding_transcript_exon_variant	2/2	3
USH2A	ENST00000674083.1	c.7342C>G	p.Pro2448Ala	missense_variant	39/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727052

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.022	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.46		Loss of glycosylation at P2448 (P = 0.0167);
MVP		0.95
MPC		0.22
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.17
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553274535; hg19: chr1-216074206;