NM_000541.5:c.52A>G

Variant names:

• chr2-233309241-A-G
• rs2125317872
• NM_000541.5:c.52A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000541.5(SAG):​c.52A>G​(p.Lys18Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAG NM_000541.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

Genes affected

SAG (HGNC:10521): (S-antigen visual arrestin) Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. S-arrestin, also known as S-antigen, is a major soluble photoreceptor protein that is involved in desensitization of the photoactivated transduction cascade. It is expressed in the retina and the pineal gland and inhibits coupling of rhodopsin to transducin in vitro. Additionally, S-arrestin is highly antigenic, and is capable of inducing experimental autoimmune uveoretinitis. Mutations in this gene have been associated with Oguchi disease, a rare autosomal recessive form of night blindness. [provided by RefSeq, Jul 2008]

SAG Gene-Disease associations (from GenCC):

• retinitis pigmentosa 47

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Oguchi disease-1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 96

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinal disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Oguchi disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000541.5. 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
	SAG	NM_000541.5	MANE Select	c.52A>G	p.Lys18Glu	missense	Exon 2 of 16	NP_000532.2	P10523

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAG	ENST00000409110.6	TSL:5 MANE Select	c.52A>G	p.Lys18Glu	missense	Exon 2 of 16	ENSP00000386444.1	P10523
	SAG	ENST00000462487.5	TSL:1	n.144+1219A>G		intron	N/A
	SAG	ENST00000447536.5	TSL:3	c.52A>G	p.Lys18Glu	missense	Exon 2 of 7	ENSP00000408937.1	E7ESX4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.90	P
Vest4		0.76
MutPred		0.58		Loss of methylation at K18 (P = 3e-04)
MVP		0.41
MPC		0.53
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.90
gMVP		0.78
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2125317872; hg19: chr2-234217887;