1-215817098-G-C

Position:

• chr1-215817098-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_206933.4(USH2A):​c.9469C>G​(p.Gln3157Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42

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 2 ACMG points.

• PM1: In a domain Fibronectin type-III 18 (size 96) in uniprot entity USH2A_HUMAN there are 24 pathogenic changes around while only 8 benign (75%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10631046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9469C>G	p.Gln3157Glu	missense_variant	48/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9469C>G	p.Gln3157Glu	missense_variant	48/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9469C>G	p.Gln3157Glu	missense_variant	48/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250496 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135354

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460800 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.4
DANN	Benign	0.53
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.032
Sift	Benign	0.40	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.19
MutPred		0.42		Gain of loop (P = 0.1069);
MVP		0.65
MPC		0.034
ClinPred		0.049	T
GERP RS		3.4
Varity_R		0.063
gMVP		0.24

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: rs772100045; hg19: chr1-215990440;