1-216185060-G-A

Variant names:

• chr1-216185060-G-A
• rs2034960
• NM_206933.4:c.4396+5163C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_206933.4(USH2A):​c.4396+5163C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,628 control chromosomes in the GnomAD database, including 25,479 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25479 hom., cov: 32)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.961
• Publications: 1 publications found

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]

USH2A Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4396+5163C>T		intron_variant	Intron 20 of 71	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4396+5163C>T		intron_variant	Intron 20 of 20		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4396+5163C>T		intron_variant	Intron 20 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.4396+5163C>T		intron_variant	Intron 20 of 20	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.4396+5163C>T		intron_variant	Intron 20 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85464 AN: 151510 Hom.: 25467 Cov.: 32

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.573

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.564 AC: 85496 AN: 151628 Hom.: 25479 Cov.: 32 AF XY: 0.573 AC XY: 42416 AN XY: 74046

African (AFR) AF: 0.358 AC: 14784 AN: 41352

American (AMR) AF: 0.643 AC: 9775 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1970 AN: 3470

East Asian (EAS) AF: 0.762 AC: 3906 AN: 5128

South Asian (SAS) AF: 0.693 AC: 3333 AN: 4812

European-Finnish (FIN) AF: 0.727 AC: 7669 AN: 10548

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 41961 AN: 67816

Other (OTH) AF: 0.575 AC: 1209 AN: 2104

Alfa AF: 0.587 Hom.: 3384

Bravo AF: 0.550

Asia WGS AF: 0.692 AC: 2406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		0.96
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2034960; hg19: chr1-216358402; COSMIC: COSV56346112;