1-215680343-C-T

Position:

• chr1-215680343-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_206933.4(USH2A):​c.12100G>A​(p.Glu4034Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

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 4 ACMG points.

• PM1: In a domain Fibronectin type-III 25 (size 103) in uniprot entity USH2A_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.12100G>A	p.Glu4034Lys	missense_variant	62/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.12100G>A	p.Glu4034Lys	missense_variant	62/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.12100G>A	p.Glu4034Lys	missense_variant	62/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.13
Sift	Benign	0.35	T
Sift4G	Benign	0.34	T
Polyphen		0.10	B
Vest4		0.20
MutPred		0.57		Gain of ubiquitination at E4034 (P = 0.0428);
MVP		0.90
MPC		0.038
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.56

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: rs794729203; hg19: chr1-215853685;