rs646094

Variant names:

• chr1-216198592-A-C
• rs646094
• NM_206933.4:c.3812-8T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-216198592-A-C
• chr1-216198592-A-T

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.3812-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,608,604 control chromosomes in the GnomAD database, including 41,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3260 hom., cov: 32)
  • Exomes 𝑓: 0.23 (37962 hom.)
• Consequence: USH2A NM_206933.4 splice_region, intron
• Scores: Splicing: ADA: 0.002956
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.63
• Publications: 17 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-216198592-A-C is Benign according to our data. Variant chr1-216198592-A-C is described in ClinVar as Benign. ClinVar VariationId is 48508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 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.3812-8T>G		splice_region intron	N/A	NP_996816.3
	USH2A	NM_007123.6		c.3812-8T>G		splice_region intron	N/A	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.3812-8T>G		splice_region intron	N/A	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.3812-8T>G		splice_region intron	N/A	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.3812-8T>G		splice_region intron	N/A	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31090 AN: 151976 Hom.: 3257 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.213 AC: 52476 AN: 246022 AF XY: 0.217

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.226 AC: 329796 AN: 1456510 Hom.: 37962 Cov.: 32 AF XY: 0.228 AC XY: 165060 AN XY: 724752

African (AFR) AF: 0.160 AC: 5361 AN: 33432

American (AMR) AF: 0.190 AC: 8495 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5885 AN: 26102

East Asian (EAS) AF: 0.191 AC: 7555 AN: 39570

South Asian (SAS) AF: 0.232 AC: 19996 AN: 86160

European-Finnish (FIN) AF: 0.160 AC: 8157 AN: 51112

Middle Eastern (MID) AF: 0.212 AC: 1206 AN: 5700

European-Non Finnish (NFE) AF: 0.234 AC: 260021 AN: 1109570

Other (OTH) AF: 0.218 AC: 13120 AN: 60268

GnomAD4 genome AF: 0.204 AC: 31103 AN: 152094 Hom.: 3260 Cov.: 32 AF XY: 0.201 AC XY: 14917 AN XY: 74334

African (AFR) AF: 0.164 AC: 6798 AN: 41516

American (AMR) AF: 0.209 AC: 3187 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 767 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1137 AN: 5160

South Asian (SAS) AF: 0.220 AC: 1061 AN: 4820

European-Finnish (FIN) AF: 0.143 AC: 1508 AN: 10578

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16013 AN: 67946

Other (OTH) AF: 0.208 AC: 440 AN: 2114

Alfa AF: 0.223 Hom.: 1542

Bravo AF: 0.204

Asia WGS AF: 0.185 AC: 643 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Usher syndrome type 2A (3)
-	-	2	not provided (2)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.4
DANN	Benign	0.73
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.14		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: rs646094; hg19: chr1-216371934; COSMIC: COSV107318880; COSMIC: COSV107318880;