NM_206933.4:c.1931A>T

Variant names:

• chr1-216289320-T-A
• rs1805048
• NM_206933.4:c.1931A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.1931A>T​(p.Asp644Val) variant causes a missense change. The variant allele was found at a frequency of 0.0665 in 1,613,914 control chromosomes in the GnomAD database, including 4,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D644D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.050 (301 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3759 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 6.89
• Publications: 19 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 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007833093).
• BP6: Variant 1-216289320-T-A is Benign according to our data. Variant chr1-216289320-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.1931A>T	p.Asp644Val	missense	Exon 11 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.1931A>T	p.Asp644Val	missense	Exon 11 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.1931A>T	p.Asp644Val	missense	Exon 11 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.1931A>T	p.Asp644Val	missense	Exon 11 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.1931A>T	p.Asp644Val	missense	Exon 11 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7682 AN: 152136 Hom.: 302 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.0709

GnomAD2 exomes AF: 0.0581 AC: 14602 AN: 251344 AF XY: 0.0613

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0389

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.000599

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0776

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0681 AC: 99598 AN: 1461660 Hom.: 3759 Cov.: 32 AF XY: 0.0692 AC XY: 50311 AN XY: 727152

African (AFR) AF: 0.0127 AC: 426 AN: 33474

American (AMR) AF: 0.0409 AC: 1829 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3409 AN: 26128

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39676

South Asian (SAS) AF: 0.0586 AC: 5055 AN: 86252

European-Finnish (FIN) AF: 0.0325 AC: 1735 AN: 53416

Middle Eastern (MID) AF: 0.144 AC: 829 AN: 5768

European-Non Finnish (NFE) AF: 0.0737 AC: 81922 AN: 1111838

Other (OTH) AF: 0.0724 AC: 4373 AN: 60384

GnomAD4 genome AF: 0.0505 AC: 7683 AN: 152254 Hom.: 301 Cov.: 32 AF XY: 0.0485 AC XY: 3612 AN XY: 74432

African (AFR) AF: 0.0144 AC: 597 AN: 41572

American (AMR) AF: 0.0490 AC: 749 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0592 AC: 285 AN: 4816

European-Finnish (FIN) AF: 0.0282 AC: 299 AN: 10612

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0742 AC: 5048 AN: 67994

Other (OTH) AF: 0.0702 AC: 148 AN: 2108

Alfa AF: 0.0737 Hom.: 381

Bravo AF: 0.0507

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0680 AC: 262

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.0577 AC: 7008

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.0909

EpiControl AF: 0.0879

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Usher syndrome type 2A (3)
-	-	2	not provided (3)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.9
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Benign	0.35	T
Sift4G	Uncertain	0.024	D
Polyphen		0.64	P
Vest4		0.23
MPC		0.040
ClinPred		0.035	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.73
Mutation Taster		=88/12	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: rs1805048; hg19: chr1-216462662; COSMIC: COSV56370431;