1-216250961-A-G

Variant names:

• chr1-216250961-A-G
• rs45555435
• NM_206933.4:c.2109T>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.2109T>C​(p.Asp703Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,916 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.017 (280 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.19
• 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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=-0.48).
• BP6: Variant 1-216250961-A-G is Benign according to our data. Variant chr1-216250961-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0146 (2219/152280) while in subpopulation AMR AF = 0.0169 (258/15302). AF 95% confidence interval is 0.016. There are 31 homozygotes in GnomAd4. There are 1157 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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.2109T>C	p.Asp703Asp	synonymous	Exon 12 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.2109T>C	p.Asp703Asp	synonymous	Exon 12 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.2109T>C	p.Asp703Asp	synonymous	Exon 12 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.2109T>C	p.Asp703Asp	synonymous	Exon 12 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.2109T>C	p.Asp703Asp	synonymous	Exon 12 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2218 AN: 152162 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0170 AC: 4261 AN: 250960 AF XY: 0.0176

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0171 AC: 25061 AN: 1461636 Hom.: 280 Cov.: 32 AF XY: 0.0170 AC XY: 12350 AN XY: 727132

African (AFR) AF: 0.00263 AC: 88 AN: 33478

American (AMR) AF: 0.0134 AC: 601 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 833 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0104 AC: 901 AN: 86256

European-Finnish (FIN) AF: 0.0457 AC: 2440 AN: 53406

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5766

European-Non Finnish (NFE) AF: 0.0170 AC: 18881 AN: 1111850

Other (OTH) AF: 0.0192 AC: 1158 AN: 60388

GnomAD4 genome AF: 0.0146 AC: 2219 AN: 152280 Hom.: 31 Cov.: 32 AF XY: 0.0155 AC XY: 1157 AN XY: 74454

African (AFR) AF: 0.00310 AC: 129 AN: 41566

American (AMR) AF: 0.0169 AC: 258 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4826

European-Finnish (FIN) AF: 0.0461 AC: 489 AN: 10602

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1142 AN: 68012

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0160 Hom.: 38

Bravo AF: 0.0121

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	3	Usher syndrome type 2A (3)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.53
PhyloP100		3.2
Mutation Taster		=96/4	polymorphism (auto)

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: rs45555435; hg19: chr1-216424303; COSMIC: COSV108138127;