Variant 1-216199854-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_206933.4(USH2A):c.3584G>C(p.Cys1195Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1195F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Variant links:

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 links:

USH2A-AS1 (HGNC:):

USH2A-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 96) in uniprot entity USH2A_HUMAN there are 24 pathogenic changes around while only 7 benign (77%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.3584G>C	p.Cys1195Ser	missense_variant	17/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.3584G>C	p.Cys1195Ser	missense_variant	17/72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.3584G>C	p.Cys1195Ser	missense_variant	17/21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.3584G>C	p.Cys1195Ser	missense_variant	17/73			ENSP00000501296.1	O75445-3
USH2A-AS1	ENST00000420867.1 linkuse as main transcript	n.362+3929C>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2018

The p.Cys1195Ser variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome and was absent from large population studi es. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, the clinical sig nificance of the p.Cys1195Ser variant is uncertain. ACMG/AMP Criteria applied: P M2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.36

Sift

Benign

0.32

T;T

Sift4G

Benign

0.14

T;D

Polyphen

0.99

D;D

Vest4

0.79

MutPred

0.54

Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);

MVP

0.89

MPC

0.057

ClinPred

0.92

GERP RS

4.3

Varity_R

0.28

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over