rs114402911

Variant names:

• chr1-216046516-C-A
• rs114402911
• NM_206933.4:c.6240G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216046516-C-A
• chr1-216046516-C-G
• chr1-216046516-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):​c.6240G>T​(p.Lys2080Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,613,826 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2080E) has been classified as Uncertain significance. The gene USH2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0073 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (52 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: 0.412
• Publications: 18 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

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008006275).
• BP6: Variant 1-216046516-C-A is Benign according to our data. Variant chr1-216046516-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 Unknown,AR,AD 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.6240G>T	p.Lys2080Asn	missense	Exon 32 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.6240G>T	p.Lys2080Asn	missense	Exon 32 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.6240G>T	p.Lys2080Asn	missense	Exon 32 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1111 AN: 152098 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00734

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00556 AC: 1396 AN: 251140 AF XY: 0.00520

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00780

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00700 AC: 10236 AN: 1461610 Hom.: 52 Cov.: 34 AF XY: 0.00680 AC XY: 4946 AN XY: 727110

African (AFR) AF: 0.00974 AC: 326 AN: 33468

American (AMR) AF: 0.00479 AC: 214 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00742 AC: 194 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86250

European-Finnish (FIN) AF: 0.00198 AC: 106 AN: 53414

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5764

European-Non Finnish (NFE) AF: 0.00798 AC: 8874 AN: 1111798

Other (OTH) AF: 0.00674 AC: 407 AN: 60388

GnomAD4 genome AF: 0.00730 AC: 1111 AN: 152216 Hom.: 9 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74428

African (AFR) AF: 0.00949 AC: 394 AN: 41530

American (AMR) AF: 0.00955 AC: 146 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00734 AC: 499 AN: 67998

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00724 Hom.: 11

Bravo AF: 0.00775

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00592 AC: 719

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	3	Usher syndrome type 2A (3)
-	1	-	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.41
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.041	D
Sift4G	Uncertain	0.013	D
Polyphen		0.88	P
Vest4		0.087
MutPred		0.47		Loss of methylation at K2080 (P = 3e-04)
MVP		0.87
MPC		0.046
ClinPred		0.025	T
GERP RS		0.71
Varity_R		0.12
gMVP		0.42
Mutation Taster		=85/15	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: rs114402911; hg19: chr1-216219858;