rs397518024

Variant names:

• chr1-216048647-C-A
• NM_206933.4:c.6050G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216048647-C-A
• chr1-216048647-C-T

Variant summary

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

The NM_206933.4(USH2A):​c.6050G>T​(p.Gly2017Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2017D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 missense, splice_region
• Scores: Splicing: ADA: 0.1713
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62

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, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.6050G>T	p.Gly2017Val	missense_variant, splice_region_variant	Exon 31 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.6050G>T	p.Gly2017Val	missense_variant, splice_region_variant	Exon 31 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.6050G>T	p.Gly2017Val	missense_variant, splice_region_variant	Exon 31 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726960

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.89	P
Vest4		0.77
MutPred		0.52		Loss of catalytic residue at T2016 (P = 0.1568);
MVP		0.96
MPC		0.25
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.52
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-216221989;