1-216084723-A-G

Variant names:

• chr1-216084723-A-G
• rs143546878
• NM_206933.4:c.5142T>C

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.5142T>C​(p.Asn1714Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 1,613,344 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (8 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.14
• Publications: 6 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-216084723-A-G is Benign according to our data. Variant chr1-216084723-A-G is described in ClinVar as Benign. ClinVar VariationId is 48529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000874 (133/152238) while in subpopulation EAS AF = 0.0199 (103/5166). AF 95% confidence interval is 0.0168. There are 1 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.5142T>C	p.Asn1714Asn	synonymous	Exon 25 of 72	NP_996816.3	O75445-1
	USH2A-AS2	NR_125992.1		n.266-1999A>G		intron	N/A
	USH2A-AS2	NR_125993.1		n.137-1999A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5142T>C	p.Asn1714Asn	synonymous	Exon 25 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.5142T>C	p.Asn1714Asn	synonymous	Exon 25 of 73	ENSP00000501296.1	O75445-3
	USH2A	ENST00000463147.1	TSL:2	n.386T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0201

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00164 AC: 411 AN: 250536 AF XY: 0.00150

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1461106 Hom.: 8 Cov.: 30 AF XY: 0.000625 AC XY: 454 AN XY: 726866

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.0000896 AC: 4 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0168 AC: 665 AN: 39676

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111614

Other (OTH) AF: 0.00215 AC: 130 AN: 60346

GnomAD4 genome AF: 0.000874 AC: 133 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15274

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

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5166

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.52
DANN	Benign	0.63
PhyloP100		-4.1
Mutation Taster		=100/0	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: rs143546878; hg19: chr1-216258065; COSMIC: COSV56336674;