1-216323502-C-A

Position:

• chr1-216323502-C-A

Variant summary

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

The ENST00000307340.8(USH2A):​c.1522G>T​(p.Ala508Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A508T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A ENST00000307340.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000307340.8
• 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.1522G>T	p.Ala508Ser	missense_variant	8/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1522G>T	p.Ala508Ser	missense_variant	8/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1522G>T	p.Ala508Ser	missense_variant	8/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.1522G>T	p.Ala508Ser	missense_variant	8/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.1522G>T	p.Ala508Ser	missense_variant	8/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461386 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727004

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.083
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.14
Sift	Benign	0.041	D;T
Sift4G	Benign	0.064	T;T
Polyphen		0.93	P;B
Vest4		0.41
MutPred		0.81		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.67
MPC		0.15
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397517999; hg19: chr1-216496844;