rs1553252388

Variant names:

• chr1-215674564-AGAGTCCATGTTC-CAAG
• rs1553252388
• NM_206933.4:c.13335_13347delGAACATGGACTCTinsCTTG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_206933.4(USH2A):​c.13335_13347delGAACATGGACTCTinsCTTG​(p.Glu4445_Ser4449delinsAspLeu) variant causes a missense, disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E4445E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.09
• Publications: 6 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 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_206933.4.
• PP5: Variant 1-215674564-AGAGTCCATGTTC-CAAG is Pathogenic according to our data. Variant chr1-215674564-AGAGTCCATGTTC-CAAG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense disruptive_inframe_deletion	N/A	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense disruptive_inframe_deletion	N/A	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense disruptive_inframe_deletion	N/A	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
3	-	-	Retinitis pigmentosa 39 (3)
2	-	-	Retinal dystrophy (2)
2	-	-	Retinitis pigmentosa (2)
2	-	-	Usher syndrome type 2A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=8/192	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs1553252388; hg19: chr1-215847906;