1-216190379-AAAAGAAAGAAAG-AAAAGAAAG

Variant names:

• chr1-216190379-AAAAG-A
• rs372388546
• NM_206933.4:c.4252-16_4252-13delCTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.4252-16_4252-13delCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00702 in 1,597,562 control chromosomes in the GnomAD database, including 524 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.034 (282 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (242 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.46
• Publications: 1 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

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-216190379-AAAAG-A is Benign according to our data. Variant chr1-216190379-AAAAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

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.4252-16_4252-13delCTTT		intron	N/A	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.4252-16_4252-13delCTTT		intron	N/A	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4252-16_4252-13delCTTT		intron	N/A	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.4252-16_4252-13delCTTT		intron	N/A	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.4252-16_4252-13delCTTT		intron	N/A	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5103 AN: 151604 Hom.: 277 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.00955 AC: 2339 AN: 244842 AF XY: 0.00742

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00693

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.000501

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000935

Gnomad OTH exome AF: 0.00518

GnomAD4 exome AF: 0.00421 AC: 6090 AN: 1445842 Hom.: 242 AF XY: 0.00379 AC XY: 2728 AN XY: 719300

African (AFR) AF: 0.121 AC: 3994 AN: 33074

American (AMR) AF: 0.00807 AC: 356 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.000661 AC: 17 AN: 25702

East Asian (EAS) AF: 0.000771 AC: 30 AN: 38890

South Asian (SAS) AF: 0.00177 AC: 151 AN: 85206

European-Finnish (FIN) AF: 0.00110 AC: 57 AN: 51644

Middle Eastern (MID) AF: 0.00778 AC: 42 AN: 5400

European-Non Finnish (NFE) AF: 0.000765 AC: 843 AN: 1102294

Other (OTH) AF: 0.0101 AC: 600 AN: 59508

GnomAD4 genome AF: 0.0338 AC: 5130 AN: 151720 Hom.: 282 Cov.: 31 AF XY: 0.0323 AC XY: 2395 AN XY: 74142

African (AFR) AF: 0.116 AC: 4796 AN: 41360

American (AMR) AF: 0.0130 AC: 197 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 67866

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.00272 Hom.: 1

Bravo AF: 0.0377

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa 39 (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372388546; hg19: chr1-216363721;