rs147039836

chr1-216046520-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):c.6236A>C(p.Lys2079Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,613,896 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.145

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002841115).
• BP6: Variant 1-216046520-T-G is Benign according to our data. Variant chr1-216046520-T-G is described in ClinVar as [Benign]. Clinvar id is 227145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216046520-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.6236A>C	p.Lys2079Thr	missense_variant	32/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.6236A>C	p.Lys2079Thr	missense_variant	32/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.6236A>C	p.Lys2079Thr	missense_variant	32/73

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00833

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000665 AC: 167 AN: 251170 Hom.: 2 AF XY: 0.000494 AC XY: 67 AN XY: 135718

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1461628 Hom.: 2 Cov.: 34 AF XY: 0.000198 AC XY: 144 AN XY: 727122

Gnomad4 AFR exome AF: 0.00864

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74456

Gnomad4 AFR AF: 0.00830

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000417 Hom.: 0

Bravo AF: 0.00260

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Lys2079Thr in Exon 32 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (31/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs147039836). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	9.2
Dann	Uncertain	0.98
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.040
Sift	Benign	0.54	T
Sift4G	Uncertain	0.059	T
Polyphen		0.20	B
Vest4		0.18
MVP		0.74
MPC		0.034
ClinPred		0.0013	T
GERP RS		0.25
Varity_R		0.058
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs147039836; hg19: chr1-216219862;