1-216190379-AAAAGAAAGAAAG-AAAAGAAAGAAAGAAAG

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_206933.4(USH2A):​c.4252-16_4252-13dupCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,609,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.0890

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-216190379-A-AAAAG is Benign according to our data. Variant chr1-216190379-A-AAAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295427.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4252-16_4252-13dupCTTT		intron_variant	Intron 19 of 71	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4252-16_4252-13dupCTTT		intron_variant	Intron 19 of 20		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4252-13_4252-12insCTTT		intron_variant	Intron 19 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.4252-13_4252-12insCTTT		intron_variant	Intron 19 of 20	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.4252-13_4252-12insCTTT		intron_variant	Intron 19 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.000659 AC: 100 AN: 151652 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000596 AC: 146 AN: 244842 Hom.: 0 AF XY: 0.000521 AC XY: 69 AN XY: 132502

Gnomad AFR exome AF: 0.000946

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00172

Gnomad SAS exome AF: 0.000398

Gnomad FIN exome AF: 0.000402

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000515 AC: 750 AN: 1457366 Hom.: 0 Cov.: 32 AF XY: 0.000501 AC XY: 363 AN XY: 725138

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.000696

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000961

Gnomad4 SAS exome AF: 0.000465

Gnomad4 FIN exome AF: 0.000535

Gnomad4 NFE exome AF: 0.000480

Gnomad4 OTH exome AF: 0.000599

GnomAD4 genome AF: 0.000659 AC: 100 AN: 151768 Hom.: 0 Cov.: 31 AF XY: 0.000701 AC XY: 52 AN XY: 74164

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Retinitis Pigmentosa, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.4252-16_4252-13dupCTTT alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0006 in 244842 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0006 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4252-16_4252-13dupCTTT in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 295427). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs372388546; hg19: chr1-216363721;