rs727505116

Variant names:

• chr1-216084853-C-A
• rs727505116
• NM_206933.4:c.5012G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216084853-C-A
• chr1-216084853-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_206933.4(USH2A):​c.5012G>T​(p.Gly1671Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1671D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.54
• Publications: 3 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-216084853-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 179773.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-216084853-C-A is Pathogenic according to our data. Variant chr1-216084853-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1439079.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.5012G>T	p.Gly1671Val	missense	Exon 25 of 72	NP_996816.3
	USH2A-AS2	NR_125992.1		n.266-1869C>A		intron	N/A
	USH2A-AS2	NR_125993.1		n.137-1869C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5012G>T	p.Gly1671Val	missense	Exon 25 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.5012G>T	p.Gly1671Val	missense	Exon 25 of 73	ENSP00000501296.1
	USH2A	ENST00000463147.1	TSL:2	n.256G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Gain of ubiquitination at K1667 (P = 0.0689)
MVP		0.94
MPC		0.26
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.94
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727505116; hg19: chr1-216258195;