chr1-215675299-T-C

Variant names:

• chr1-215675299-T-C
• rs2797235
• NM_206933.4:c.12612A>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.12612A>G​(p.Thr4204Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 1,613,914 control chromosomes in the GnomAD database, including 503,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43060 hom., cov: 33)
  • Exomes 𝑓: 0.79 (460076 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.101
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-215675299-T-C is Benign according to our data. Variant chr1-215675299-T-C is described in ClinVar as Benign. ClinVar VariationId is 177993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 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.12612A>G	p.Thr4204Thr	synonymous	Exon 63 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.12612A>G	p.Thr4204Thr	synonymous	Exon 63 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.12612A>G	p.Thr4204Thr	synonymous	Exon 63 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113712 AN: 152030 Hom.: 43036 Cov.: 33

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.786

GnomAD2 exomes AF: 0.767 AC: 191133 AN: 249244 AF XY: 0.767

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.797

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.812

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.792 AC: 1157157 AN: 1461764 Hom.: 460076 Cov.: 89 AF XY: 0.789 AC XY: 574029 AN XY: 727172

African (AFR) AF: 0.628 AC: 21036 AN: 33478

American (AMR) AF: 0.808 AC: 36147 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20589 AN: 26136

East Asian (EAS) AF: 0.627 AC: 24884 AN: 39696

South Asian (SAS) AF: 0.701 AC: 60501 AN: 86258

European-Finnish (FIN) AF: 0.752 AC: 40122 AN: 53330

Middle Eastern (MID) AF: 0.786 AC: 4533 AN: 5768

European-Non Finnish (NFE) AF: 0.812 AC: 902412 AN: 1111982

Other (OTH) AF: 0.777 AC: 46933 AN: 60396

GnomAD4 genome AF: 0.748 AC: 113790 AN: 152150 Hom.: 43060 Cov.: 33 AF XY: 0.744 AC XY: 55328 AN XY: 74384

African (AFR) AF: 0.635 AC: 26331 AN: 41484

American (AMR) AF: 0.799 AC: 12217 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2723 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3336 AN: 5174

South Asian (SAS) AF: 0.680 AC: 3280 AN: 4824

European-Finnish (FIN) AF: 0.744 AC: 7876 AN: 10584

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55299 AN: 68006

Other (OTH) AF: 0.787 AC: 1663 AN: 2114

Alfa AF: 0.796 Hom.: 110728

Bravo AF: 0.747

Asia WGS AF: 0.654 AC: 2274 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.36
PhyloP100		0.10
Mutation Taster		=66/34	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: rs2797235; hg19: chr1-215848641; COSMIC: COSV56342874;