rs397517979

Variant names:

• chr1-216324269-C-G
• rs397517979
• NM_206933.4:c.1227G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-216324269-C-G
• chr1-216324269-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_206933.4(USH2A):​c.1227G>C​(p.Trp409Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.93
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-216324269-C-G is Pathogenic according to our data. Variant chr1-216324269-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 48393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1227G>C	p.Trp409Cys	missense_variant	Exon 7 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1227G>C	p.Trp409Cys	missense_variant	Exon 7 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1227G>C	p.Trp409Cys	missense_variant	Exon 7 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.1227G>C	p.Trp409Cys	missense_variant	Exon 7 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.1227G>C	p.Trp409Cys	missense_variant	Exon 7 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Mar 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Trp409Cys in USH2A has been identified by our laboratory in one individual w ith the features of Usher syndrome who carried a second pathogenic USH2A variant . Parental testing confirmed the presence of these two variants in trans support ing a pathogenic role for this variant. In addition, this variant has not been i dentified in large and broad populations by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS/). Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Tr p409Cys variant is more likely to impact the protein, though this information is not predictive enough to assume pathogenicity. In summary, this variant is like ly to be pathogenic due to its presence in trans with a second pathogenic USH2A variant in an affected individual, though additional studies are required to ful ly establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.4	M;M
PhyloP100		5.9
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.93		Loss of catalytic residue at L407 (P = 0.0214);Loss of catalytic residue at L407 (P = 0.0214);
MVP		0.96
MPC		0.28
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.89
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs397517979; hg19: chr1-216497611;