NM_004937.3:c.-19-211A>G

Variant names:

• chr17-3639977-A-G
• rs456253
• NM_004937.3:c.-19-211A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004937.3(CTNS):​c.-19-211A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,970 control chromosomes in the GnomAD database, including 14,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.43 (14451 hom., cov: 32)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.157
• Publications: 2 publications found

Genes affected

CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

CTNS Gene-Disease associations (from GenCC):

• cystinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
• nephropathic cystinosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• juvenile nephropathic cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ocular cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• nephropathic infantile cystinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371493 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-3639977-A-G is Benign according to our data. Variant chr17-3639977-A-G is described in ClinVar as Benign. ClinVar VariationId is 1277327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. 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
	CTNS	NM_004937.3	MANE Select	c.-19-211A>G		intron	N/A	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.-19-211A>G		intron	N/A	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.-19-211A>G		intron	N/A	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.-19-211A>G		intron	N/A	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.-19-211A>G		intron	N/A	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.-19-211A>G		intron	N/A	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64679 AN: 151850 Hom.: 14447 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.443

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

GnomAD4 genome AF: 0.426 AC: 64713 AN: 151970 Hom.: 14451 Cov.: 32 AF XY: 0.423 AC XY: 31427 AN XY: 74296

African (AFR) AF: 0.339 AC: 14049 AN: 41426

American (AMR) AF: 0.405 AC: 6191 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1522 AN: 3468

East Asian (EAS) AF: 0.181 AC: 938 AN: 5184

South Asian (SAS) AF: 0.355 AC: 1713 AN: 4822

European-Finnish (FIN) AF: 0.507 AC: 5351 AN: 10554

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.492 AC: 33432 AN: 67932

Other (OTH) AF: 0.441 AC: 930 AN: 2108

Alfa AF: 0.406 Hom.: 2987

Bravo AF: 0.413

Asia WGS AF: 0.275 AC: 957 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.0
DANN	Benign	0.41
PhyloP100		0.16
PromoterAI		0.0047	Neutral
Mutation Taster		=100/0	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: rs456253; hg19: chr17-3543271;