1-216418592-T-C

Variant names:

• chr1-216418592-T-C
• rs73102592
• NM_206933.4:c.573A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.573A>G​(p.Val191Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,613,368 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (88 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.31
• Publications: 8 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-216418592-T-C is Benign according to our data. Variant chr1-216418592-T-C is described in ClinVar as Benign. ClinVar VariationId is 48540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0608 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.573A>G	p.Val191Val	synonymous	Exon 3 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.573A>G	p.Val191Val	synonymous	Exon 3 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.573A>G	p.Val191Val	synonymous	Exon 3 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.573A>G	p.Val191Val	synonymous	Exon 3 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.573A>G	p.Val191Val	synonymous	Exon 3 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2937 AN: 152124 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00749 AC: 1879 AN: 250906 AF XY: 0.00618

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0355

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00309 AC: 4521 AN: 1461126 Hom.: 88 Cov.: 30 AF XY: 0.00289 AC XY: 2100 AN XY: 726838

African (AFR) AF: 0.0597 AC: 1997 AN: 33428

American (AMR) AF: 0.00396 AC: 177 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26108

East Asian (EAS) AF: 0.0336 AC: 1332 AN: 39644

South Asian (SAS) AF: 0.00163 AC: 141 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00608 AC: 35 AN: 5758

European-Non Finnish (NFE) AF: 0.000331 AC: 368 AN: 1111568

Other (OTH) AF: 0.00757 AC: 457 AN: 60356

GnomAD4 genome AF: 0.0194 AC: 2952 AN: 152242 Hom.: 79 Cov.: 32 AF XY: 0.0185 AC XY: 1380 AN XY: 74428

African (AFR) AF: 0.0628 AC: 2609 AN: 41542

American (AMR) AF: 0.00602 AC: 92 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0379 AC: 196 AN: 5166

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68016

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0105 Hom.: 25

Bravo AF: 0.0217

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Usher syndrome type 2A (3)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.0
DANN	Benign	0.82
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73102592; hg19: chr1-216591934; COSMIC: COSV107317774;