chr1-216289285-C-T

Variant names:

• chr1-216289285-C-T
• rs146824138
• NM_206933.4:c.1966G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1966G>A (p.Asp656Asn) variant in USH2A is 0.09251% (1246/1613836 CI 95%) of European (Non Finnish) alleles in gnomAD v4, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The variant has been identified in 3 probands with hearing loss and 2 probands with Usher syndrome (SCV000065500.6; PMID:16963483); however an alternate cause of hearing loss in other genes was identified in 3 probands (SCV000065500.6), and a second variant in USH2A was not identified in the other two probands (SCV000065500.6; PMID:16963483). Finally, in the last proband, another likely benign variant was identified with phasing unknown (SCV000065500.6). Altogether, this evidence does not meet the criteria set to apply PM3_Supporting. Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, the c.1966G>A (p.Asp656Asn) variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA143431/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:10 B:8
• Conservation: PhyloP100: 2.50
• 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 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.1966G>A	p.Asp656Asn	missense	Exon 11 of 72	NP_996816.3
	USH2A	NM_007123.6		c.1966G>A	p.Asp656Asn	missense	Exon 11 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.1966G>A	p.Asp656Asn	missense	Exon 11 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.1966G>A	p.Asp656Asn	missense	Exon 11 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.1966G>A	p.Asp656Asn	missense	Exon 11 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000605 AC: 152 AN: 251290 AF XY: 0.000545

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000782 AC: 1143 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.000740 AC XY: 538 AN XY: 727092

African (AFR) AF: 0.000179 AC: 6 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000964 AC: 1072 AN: 1111766

Other (OTH) AF: 0.000464 AC: 28 AN: 60376

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74460

African (AFR) AF: 0.000192 AC: 8 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000829 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000758 AC: 92

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	3	-	Usher syndrome type 2A (3)
-	2	-	Retinal dystrophy (2)
-	2	-	Retinitis pigmentosa (2)
-	1	-	Amblyopia;C0431399:Joubert syndrome;C0454644:Delayed speech and language development;C1842688:Hypoplasia of the brainstem;C1854301:Motor delay;C1865866:Congenital sensorineural hearing impairment;C4022154:Cerebellar hemisphere hypoplasia;C5231391:Congenital cerebellar hypoplasia (1)
-	-	1	not specified (1)
-	-	1	USH2A-related disorder (1)
-	-	1	Usher syndrome (1)
-	-	1	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.073
Sift	Benign	0.040	D
Sift4G	Uncertain	0.030	D
Polyphen		0.14	B
Vest4		0.74
MVP		0.90
MPC		0.049
ClinPred		0.035	T
GERP RS		4.2
Varity_R		0.063
gMVP		0.53
Mutation Taster		=10/90	disease causing

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: rs146824138; hg19: chr1-216462627;