1-216196630-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_206933.4(USH2A):c.4174G>C(p.Gly1392Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Fibronectin type-III 4 (size 104) in uniprot entity USH2A_HUMAN there are 34 pathogenic changes around while only 6 benign (85%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.4174G>C	p.Gly1392Arg	missense_variant	19/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+705C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.4174G>C	p.Gly1392Arg	missense_variant	19/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.4174G>C	p.Gly1392Arg	missense_variant	19/21	1
USH2A-AS1	ENST00000420867.1	n.362+705C>G		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.4174G>C	p.Gly1392Arg	missense_variant	19/73

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.00090	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.82		Gain of methylation at K1393 (P = 0.0238);Gain of methylation at K1393 (P = 0.0238);
MVP		0.97
MPC		0.25
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1177198729; hg19: chr1-216369972;