rs12404427

Variant names:

• chr1-215900163-C-T
• rs12404427
• NM_206933.4:c.7506G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.7506G>A​(p.Pro2502Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,613,400 control chromosomes in the GnomAD database, including 6,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.075 (470 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5609 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.03
• 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 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

ENSG00000229242 (HGNC:):

ACMG classification

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-215900163-C-T is Benign according to our data. Variant chr1-215900163-C-T is described in ClinVar as Benign. ClinVar VariationId is 48584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0816 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.7506G>A	p.Pro2502Pro	synonymous	Exon 40 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.7506G>A	p.Pro2502Pro	synonymous	Exon 40 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.7506G>A	p.Pro2502Pro	synonymous	Exon 40 of 73	ENSP00000501296.1	O75445-3
	ENSG00000229242	ENST00000414995.1	TSL:3	n.61-562C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11471 AN: 151954 Hom.: 470 Cov.: 33

Gnomad AFR AF: 0.0816

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0684 AC: 17142 AN: 250672 AF XY: 0.0676

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0782

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0835 AC: 121987 AN: 1461328 Hom.: 5609 Cov.: 32 AF XY: 0.0823 AC XY: 59840 AN XY: 726974

African (AFR) AF: 0.0809 AC: 2707 AN: 33446

American (AMR) AF: 0.0916 AC: 4095 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0393 AC: 1027 AN: 26112

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39676

South Asian (SAS) AF: 0.0582 AC: 5022 AN: 86258

European-Finnish (FIN) AF: 0.0521 AC: 2782 AN: 53378

Middle Eastern (MID) AF: 0.0331 AC: 191 AN: 5766

European-Non Finnish (NFE) AF: 0.0915 AC: 101667 AN: 1111652

Other (OTH) AF: 0.0740 AC: 4467 AN: 60352

GnomAD4 genome AF: 0.0755 AC: 11478 AN: 152072 Hom.: 470 Cov.: 33 AF XY: 0.0736 AC XY: 5473 AN XY: 74334

African (AFR) AF: 0.0816 AC: 3387 AN: 41484

American (AMR) AF: 0.0843 AC: 1286 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5170

South Asian (SAS) AF: 0.0537 AC: 259 AN: 4822

European-Finnish (FIN) AF: 0.0502 AC: 530 AN: 10564

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5674 AN: 67982

Other (OTH) AF: 0.0621 AC: 131 AN: 2110

Alfa AF: 0.0771 Hom.: 872

Bravo AF: 0.0760

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0751

EpiControl AF: 0.0759

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.81
PhyloP100		-2.0
Mutation Taster		=100/0	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: rs12404427; hg19: chr1-216073505; COSMIC: COSV56327776;