1-215674135-C-G

Position:

• chr1-215674135-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_206933.4(USH2A):​c.13776G>C​(p.Gln4592His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4592R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.46

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.13776G>C	p.Gln4592His	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.13776G>C	p.Gln4592His	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.13776G>C	p.Gln4592His	missense_variant	63/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461846 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 18, 2024

Variant summary: USH2A c.13776G>C (p.Gln4592His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251212 control chromosomes (gnomAD). c.13776G>C has been reported in the literature in individuals affected with Usher Syndrome (e.g. Dreyer_2008, Dad_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18273898, 27957503). ClinVar contains an entry for this variant (Variation ID: 554572). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.29
Sift	Benign	0.083	T
Sift4G	Uncertain	0.015	D
Polyphen		0.90	P
Vest4		0.72
MutPred		0.55		Gain of disorder (P = 0.1025);
MVP		0.89
MPC		0.15
ClinPred		0.27	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1350039852; hg19: chr1-215847477; COSMIC: COSV105883215;