NM_206933.4:c.504A>G

Variant names:

• chr1-216418661-T-C
• rs4253963
• NM_206933.4:c.504A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.504A>G​(p.Thr168Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,612,398 control chromosomes in the GnomAD database, including 341,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29448 hom., cov: 31)
  • Exomes 𝑓: 0.65 (311915 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.565
• Publications: 41 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-216418661-T-C is Benign according to our data. Variant chr1-216418661-T-C is described in ClinVar as Benign. ClinVar VariationId is 48528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.565 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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.504A>G	p.Thr168Thr	synonymous	Exon 3 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.504A>G	p.Thr168Thr	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.504A>G	p.Thr168Thr	synonymous	Exon 3 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.504A>G	p.Thr168Thr	synonymous	Exon 3 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.504A>G	p.Thr168Thr	synonymous	Exon 3 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93643 AN: 151692 Hom.: 29431 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.653 AC: 163677 AN: 250764 AF XY: 0.648

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.694

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.839

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.647

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.651 AC: 951291 AN: 1460588 Hom.: 311915 Cov.: 55 AF XY: 0.648 AC XY: 471157 AN XY: 726636

African (AFR) AF: 0.492 AC: 16440 AN: 33394

American (AMR) AF: 0.692 AC: 30921 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14831 AN: 26084

East Asian (EAS) AF: 0.851 AC: 33714 AN: 39626

South Asian (SAS) AF: 0.602 AC: 51933 AN: 86232

European-Finnish (FIN) AF: 0.693 AC: 36984 AN: 53348

Middle Eastern (MID) AF: 0.515 AC: 2967 AN: 5758

European-Non Finnish (NFE) AF: 0.653 AC: 725249 AN: 1111182

Other (OTH) AF: 0.634 AC: 38252 AN: 60312

GnomAD4 genome AF: 0.617 AC: 93701 AN: 151810 Hom.: 29448 Cov.: 31 AF XY: 0.621 AC XY: 46074 AN XY: 74156

African (AFR) AF: 0.501 AC: 20746 AN: 41402

American (AMR) AF: 0.657 AC: 10001 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1988 AN: 3468

East Asian (EAS) AF: 0.833 AC: 4253 AN: 5106

South Asian (SAS) AF: 0.624 AC: 3013 AN: 4828

European-Finnish (FIN) AF: 0.702 AC: 7416 AN: 10562

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44193 AN: 67914

Other (OTH) AF: 0.611 AC: 1286 AN: 2104

Alfa AF: 0.629 Hom.: 28842

Bravo AF: 0.610

Asia WGS AF: 0.691 AC: 2402 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	3	Usher syndrome type 2A (3)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.71
DANN	Benign	0.41
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4253963; hg19: chr1-216592003;