Variant 1-216190379-AAAAGAAAGAAAG-AAAAGAAAGAAAGAAAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0890

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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: {Uncertain_significance=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.4252-16_4252-13dupCTTT		intron_variant		ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.4252-16_4252-13dupCTTT		intron_variant			NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.4252-13_4252-12insCTTT	intron_variant	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.4252-13_4252-12insCTTT	intron_variant	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.4252-13_4252-12insCTTT	intron_variant			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000659

AC:

100

AN:

151652

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000521

AC XY:

AN XY:

132502

show subpopulations

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.:

Cov.:

AF XY:

0.000501

AC XY:

363

AN XY:

725138

show subpopulations

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.:

Cov.:

AF XY:

0.000701

AC XY:

AN XY:

74164

show subpopulations

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:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Retinitis Pigmentosa, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa-deafness syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 10, 2024

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over