rs41303257

Variant names:

• chr1-216198451-A-G
• rs41303257
• NM_206933.4:c.3945T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_206933.4(USH2A):​c.3945T>C​(p.Asn1315Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,006 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (202 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.933
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-216198451-A-G is Benign according to our data. Variant chr1-216198451-A-G is described in ClinVar as Benign. ClinVar VariationId is 48510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.933 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1802/152224) while in subpopulation SAS AF = 0.0234 (113/4828). AF 95% confidence interval is 0.0199. There are 11 homozygotes in GnomAd4. There are 873 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.3945T>C	p.Asn1315Asn	synonymous	Exon 18 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.3945T>C	p.Asn1315Asn	synonymous	Exon 18 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.3945T>C	p.Asn1315Asn	synonymous	Exon 18 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.3945T>C	p.Asn1315Asn	synonymous	Exon 18 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.3945T>C	p.Asn1315Asn	synonymous	Exon 18 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1802 AN: 152106 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00999

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0140 AC: 3523 AN: 250934 AF XY: 0.0153

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0148 AC: 21702 AN: 1461782 Hom.: 202 Cov.: 32 AF XY: 0.0154 AC XY: 11189 AN XY: 727188

African (AFR) AF: 0.00200 AC: 67 AN: 33478

American (AMR) AF: 0.00930 AC: 416 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 707 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.0217 AC: 1870 AN: 86254

European-Finnish (FIN) AF: 0.0115 AC: 616 AN: 53420

Middle Eastern (MID) AF: 0.0305 AC: 176 AN: 5768

European-Non Finnish (NFE) AF: 0.0152 AC: 16953 AN: 1111952

Other (OTH) AF: 0.0148 AC: 894 AN: 60390

GnomAD4 genome AF: 0.0118 AC: 1802 AN: 152224 Hom.: 11 Cov.: 32 AF XY: 0.0117 AC XY: 873 AN XY: 74418

African (AFR) AF: 0.00327 AC: 136 AN: 41540

American (AMR) AF: 0.0125 AC: 191 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.0234 AC: 113 AN: 4828

European-Finnish (FIN) AF: 0.00999 AC: 106 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1103 AN: 68012

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0150 Hom.: 26

Bravo AF: 0.0118

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0179

EpiControl AF: 0.0173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	3	Usher syndrome type 2A (3)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41303257; hg19: chr1-216371793; COSMIC: COSV56346147; COSMIC: COSV56346147;