1-216198326-G-C

Variant names:

• chr1-216198326-G-C
• rs201190539
• NM_206933.4:c.4070C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_206933.4(USH2A):​c.4070C>G​(p.Thr1357Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1357M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37
• Publications: 5 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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.4070C>G	p.Thr1357Arg	missense	Exon 18 of 72	NP_996816.3
	USH2A	NM_007123.6		c.4070C>G	p.Thr1357Arg	missense	Exon 18 of 21	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4070C>G	p.Thr1357Arg	missense	Exon 18 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.4070C>G	p.Thr1357Arg	missense	Exon 18 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.4070C>G	p.Thr1357Arg	missense	Exon 18 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		6.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.45	P
Vest4		0.78
MutPred		0.43		Loss of phosphorylation at T1357 (P = 0.0367)
MVP		0.97
MPC		0.070
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.75
gMVP		0.84
Mutation Taster		=6/94	disease causing

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: rs201190539; hg19: chr1-216371668; COSMIC: COSV56367603; COSMIC: COSV56367603;