chr1-215779946-G-T

Variant names:

• chr1-215779946-G-T
• rs61276761
• NM_206933.4:c.10836C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.10836C>A​(p.Val3612Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,614,020 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (197 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (178 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.773
• 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-215779946-G-T is Benign according to our data. Variant chr1-215779946-G-T is described in ClinVar as Benign. ClinVar VariationId is 48359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.092 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.10836C>A	p.Val3612Val	synonymous	Exon 55 of 72	NP_996816.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.10836C>A	p.Val3612Val	synonymous	Exon 55 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.10836C>A	p.Val3612Val	synonymous	Exon 55 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4125 AN: 152020 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00717 AC: 1803 AN: 251374 AF XY: 0.00504

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00274 AC: 4007 AN: 1461882 Hom.: 178 Cov.: 32 AF XY: 0.00235 AC XY: 1708 AN XY: 727242

African (AFR) AF: 0.0956 AC: 3202 AN: 33480

American (AMR) AF: 0.00559 AC: 250 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1112008

Other (OTH) AF: 0.00646 AC: 390 AN: 60396

GnomAD4 genome AF: 0.0272 AC: 4136 AN: 152138 Hom.: 197 Cov.: 32 AF XY: 0.0255 AC XY: 1895 AN XY: 74388

African (AFR) AF: 0.0945 AC: 3918 AN: 41454

American (AMR) AF: 0.0106 AC: 162 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0123 Hom.: 44

Bravo AF: 0.0316

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		0.77
Mutation Taster		=98/2	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: rs61276761; hg19: chr1-215953288;