rs79444516

Variant names:

• chr1-215998957-C-G
• rs79444516
• NM_206933.4:c.6587G>C

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.6587G>C​(p.Ser2196Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00684 in 1,613,082 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (347 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (276 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.186
• Publications: 12 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=0.0024485886).
• BP6: Variant 1-215998957-C-G is Benign according to our data. Variant chr1-215998957-C-G is described in ClinVar as Benign. ClinVar VariationId is 48565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 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.6587G>C	p.Ser2196Thr	missense	Exon 34 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.6587G>C	p.Ser2196Thr	missense	Exon 34 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.6587G>C	p.Ser2196Thr	missense	Exon 34 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5645 AN: 151928 Hom.: 347 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.00925 AC: 2322 AN: 250942 AF XY: 0.00658

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00368 AC: 5376 AN: 1461036 Hom.: 276 Cov.: 32 AF XY: 0.00310 AC XY: 2255 AN XY: 726854

African (AFR) AF: 0.129 AC: 4305 AN: 33428

American (AMR) AF: 0.00575 AC: 257 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5760

European-Non Finnish (NFE) AF: 0.000239 AC: 266 AN: 1111468

Other (OTH) AF: 0.00810 AC: 489 AN: 60346

GnomAD4 genome AF: 0.0373 AC: 5664 AN: 152046 Hom.: 347 Cov.: 32 AF XY: 0.0355 AC XY: 2642 AN XY: 74334

African (AFR) AF: 0.130 AC: 5408 AN: 41468

American (AMR) AF: 0.0113 AC: 172 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 67978

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.00582 Hom.: 42

Bravo AF: 0.0417

ESP6500AA AF: 0.119 AC: 524

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0115 AC: 1397

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.19
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Uncertain	0.014	D
Polyphen		0.80	P
Vest4		0.15
MPC		0.059
ClinPred		0.015	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.47
Mutation Taster		=76/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79444516; hg19: chr1-216172299; COSMIC: COSV56389740;