chr1-216199817-G-A

Position:

• chr1-216199817-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_206933.4(USH2A):​c.3621C>T​(p.Ile1207=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,184 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.352

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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-216199817-G-A is Benign according to our data. Variant chr1-216199817-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48505.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=2}. Variant chr1-216199817-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.3621C>T	p.Ile1207=	synonymous_variant	17/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+3892G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.3621C>T	p.Ile1207=	synonymous_variant	17/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.3621C>T	p.Ile1207=	synonymous_variant	17/21	1
USH2A-AS1	ENST00000420867.1	n.362+3892G>A		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.3621C>T	p.Ile1207=	synonymous_variant	17/73

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000570 AC: 143 AN: 251016 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135638

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461828 Hom.: 1 Cov.: 32 AF XY: 0.000205 AC XY: 149 AN XY: 727224

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74496

Gnomad4 AFR AF: 0.00589

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 2A Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	Ile1207Ile in exon 17 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.5% (19/3738) of Africa n American chromosomes in a broad population by the NHLBI Exome sequencing proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs146462407). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	5.3
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs146462407; hg19: chr1-216373159;