1-215844339-C-T

Variant names:

• chr1-215844339-C-T
• rs111033397
• NM_206933.4:c.9213G>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.9213G>A​(p.Ser3071Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,708 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3071S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.152
• 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 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=-0.58).
• BP6: Variant 1-215844339-C-T is Benign according to our data. Variant chr1-215844339-C-T is described in ClinVar as Benign. ClinVar VariationId is 48616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1578/152266) while in subpopulation AFR AF = 0.0354 (1469/41548). AF 95% confidence interval is 0.0339. There are 18 homozygotes in GnomAd4. There are 744 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.9213G>A	p.Ser3071Ser	synonymous	Exon 46 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.9213G>A	p.Ser3071Ser	synonymous	Exon 46 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.9213G>A	p.Ser3071Ser	synonymous	Exon 46 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1576 AN: 152148 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

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: 0.000353

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00304 AC: 763 AN: 250628 AF XY: 0.00242

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00143 AC: 2093 AN: 1461442 Hom.: 29 Cov.: 31 AF XY: 0.00131 AC XY: 950 AN XY: 727012

African (AFR) AF: 0.0408 AC: 1366 AN: 33458

American (AMR) AF: 0.00255 AC: 114 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53368

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5760

European-Non Finnish (NFE) AF: 0.000361 AC: 401 AN: 1111782

Other (OTH) AF: 0.00275 AC: 166 AN: 60386

GnomAD4 genome AF: 0.0104 AC: 1578 AN: 152266 Hom.: 18 Cov.: 33 AF XY: 0.00999 AC XY: 744 AN XY: 74464

African (AFR) AF: 0.0354 AC: 1469 AN: 41548

American (AMR) AF: 0.00465 AC: 71 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68016

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00342 Hom.: 8

Bravo AF: 0.0121

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.58
CADD	Benign	6.2
DANN	Benign	0.61
PhyloP100		-0.15
Mutation Taster		=93/7	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: rs111033397; hg19: chr1-216017681;