1-216073249-T-C

Variant names:

• chr1-216073249-T-C
• rs141609561
• NM_206933.4:c.5624A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_206933.4(USH2A):​c.5624A>G​(p.Asn1875Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1875K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.870
• Publications: 4 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-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.062033236).
• BP6: Variant 1-216073249-T-C is Benign according to our data. Variant chr1-216073249-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178579.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.5624A>G	p.Asn1875Ser	missense	Exon 28 of 72	NP_996816.3
	USH2A-AS2	NR_125992.1		n.136+649T>C		intron	N/A
	USH2A-AS2	NR_125993.1		n.136+649T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5624A>G	p.Asn1875Ser	missense	Exon 28 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.5624A>G	p.Asn1875Ser	missense	Exon 28 of 73	ENSP00000501296.1
	USH2A-AS2	ENST00000430890.5	TSL:2	n.78+443T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000980 AC: 149 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000283 AC: 71 AN: 250676 AF XY: 0.000199

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 727120

African (AFR) AF: 0.00338 AC: 113 AN: 33474

American (AMR) AF: 0.000448 AC: 20 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111930

Other (OTH) AF: 0.000364 AC: 22 AN: 60378

GnomAD4 genome AF: 0.000973 AC: 148 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74382

African (AFR) AF: 0.00320 AC: 133 AN: 41532

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.00102

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	not specified (2)
-	1	1	Usher syndrome type 2A (2)
-	-	1	USH2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.87
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.67
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.0080	B
Vest4		0.31
MVP		0.91
MPC		0.033
ClinPred		0.028	T
GERP RS		3.2
Varity_R		0.091
gMVP		0.44
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141609561; hg19: chr1-216246591;