rs78576418

Variant names:

• chr1-215650709-C-T
• rs78576418
• NM_206933.4:c.14226G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_206933.4(USH2A):​c.14226G>A​(p.Thr4742Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,613,960 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (8 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.931
• Publications: 1 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 2

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.65).
• BP6: Variant 1-215650709-C-T is Benign according to our data. Variant chr1-215650709-C-T is described in ClinVar as Benign. ClinVar VariationId is 48432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.931 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00495 (753/152078) while in subpopulation AFR AF = 0.0172 (712/41494). AF 95% confidence interval is 0.0161. There are 9 homozygotes in GnomAd4. There are 353 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.14226G>A	p.Thr4742Thr	synonymous	Exon 65 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.14226G>A	p.Thr4742Thr	synonymous	Exon 65 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.14226G>A	p.Thr4742Thr	synonymous	Exon 65 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 750 AN: 151960 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00117 AC: 294 AN: 251288 AF XY: 0.000781

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000501 AC: 733 AN: 1461882 Hom.: 8 Cov.: 33 AF XY: 0.000433 AC XY: 315 AN XY: 727246

African (AFR) AF: 0.0175 AC: 587 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.00101 AC: 61 AN: 60396

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152078 Hom.: 9 Cov.: 32 AF XY: 0.00475 AC XY: 353 AN XY: 74326

African (AFR) AF: 0.0172 AC: 712 AN: 41494

American (AMR) AF: 0.00216 AC: 33 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00317 Hom.: 1

Bravo AF: 0.00541

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Retinitis pigmentosa 39 (1)
-	-	1	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.3
DANN	Benign	0.36
PhyloP100		-0.93
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78576418; hg19: chr1-215824051;