NM_206933.4:c.11928G>A

Variant names:

• chr1-215728168-C-T
• rs55961436
• NM_206933.4:c.11928G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_206933.4(USH2A):​c.11928G>A​(p.Thr3976Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,106 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T3976T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0096 (19 hom., cov: 32)
  • Exomes 𝑓: 0.011 (128 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.43
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-215728168-C-T is Benign according to our data. Variant chr1-215728168-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48386.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

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.11928G>A	p.Thr3976Thr	synonymous	Exon 61 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.11928G>A	p.Thr3976Thr	synonymous	Exon 61 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.11928G>A	p.Thr3976Thr	synonymous	Exon 61 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1468 AN: 152108 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00952 AC: 2392 AN: 251312 AF XY: 0.00998

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.00972

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0109 AC: 15885 AN: 1461880 Hom.: 128 Cov.: 33 AF XY: 0.0108 AC XY: 7882 AN XY: 727242

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00347 AC: 155 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 55 AN: 26136

East Asian (EAS) AF: 0.000982 AC: 39 AN: 39700

South Asian (SAS) AF: 0.00544 AC: 469 AN: 86258

European-Finnish (FIN) AF: 0.0399 AC: 2130 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.0112 AC: 12411 AN: 1112004

Other (OTH) AF: 0.00907 AC: 548 AN: 60396

GnomAD4 genome AF: 0.00964 AC: 1467 AN: 152226 Hom.: 19 Cov.: 32 AF XY: 0.0110 AC XY: 822 AN XY: 74412

African (AFR) AF: 0.00222 AC: 92 AN: 41522

American (AMR) AF: 0.00634 AC: 97 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.0429 AC: 455 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0109 AC: 739 AN: 68030

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00786 Hom.: 7

Bravo AF: 0.00624

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00818

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.6
DANN	Benign	0.36
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs55961436; hg19: chr1-215901510;