chr1-215671121-G-C

Position:

• chr1-215671121-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000307340.8(USH2A):​c.13984C>G​(p.Gln4662Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,074 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: USH2A ENST00000307340.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.07

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041714907).
• BP6: Variant 1-215671121-G-C is Benign according to our data. Variant chr1-215671121-G-C is described in ClinVar as [Benign]. Clinvar id is 48424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215671121-G-C is described in Lovd as [Likely_benign]. Variant chr1-215671121-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1674/152202) while in subpopulation AFR AF= 0.0382 (1587/41516). AF 95% confidence interval is 0.0367. There are 36 homozygotes in gnomad4. There are 785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.13984C>G	p.Gln4662Glu	missense_variant	64/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13984C>G	p.Gln4662Glu	missense_variant	64/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.13984C>G	p.Gln4662Glu	missense_variant	64/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1671 AN: 152084 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00269 AC: 677 AN: 251310 Hom.: 14 AF XY: 0.00183 AC XY: 249 AN XY: 135804

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00106 AC: 1550 AN: 1461872 Hom.: 32 Cov.: 31 AF XY: 0.000843 AC XY: 613 AN XY: 727242

Gnomad4 AFR exome AF: 0.0383

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.0110 AC: 1674 AN: 152202 Hom.: 36 Cov.: 32 AF XY: 0.0105 AC XY: 785 AN XY: 74422

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00196 Hom.: 3

Bravo AF: 0.0126

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00321 AC: 390

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2011

Gln4662Glu in exon 64 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in dbSNP in 1.8% (91/5013) control chr omosomes (rs41302237). -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A 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	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.0
DANN	Benign	0.78
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.028
Sift	Benign	0.48	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.60
MPC		0.033
ClinPred		0.0015	T
GERP RS		0.63
Varity_R		0.072
gMVP		0.44

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: rs41302237; hg19: chr1-215844463;