rs386833730

Variant names:

• chr16-28486464-C-G
• rs386833730
• NM_001042432.2:c.560G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-28486464-C-G
• chr16-28486464-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001042432.2(CLN3):​c.560G>C​(p.Gly187Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G187E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.52
• Publications: 7 publications found

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001042432.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-28486464-C-G is Pathogenic according to our data. Variant chr16-28486464-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56281.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.560G>C	p.Gly187Ala	missense_variant	Exon 9 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.560G>C	p.Gly187Ala	missense_variant	Exon 9 of 16	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;D;.;.;D;.;D;D;.;.;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;.;D;.;.;D;.;D;D;.;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;H;.;.;.;.;H;.;H;.;.;.
PhyloP100		6.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	.;.;D;.;D;D;D;D;.;D;.;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;D;.;D;D;D;D;.;D;.;.;D
Sift4G	Uncertain	0.011	.;.;.;D;.;D;D;D;.;D;.;.;.
Polyphen		1.0	.;D;D;.;.;.;.;D;.;D;.;.;.
Vest4		0.92, 0.92, 0.90, 0.84
MutPred		0.98		Loss of glycosylation at S186 (P = 0.0718);Loss of glycosylation at S186 (P = 0.0718);Loss of glycosylation at S186 (P = 0.0718);Loss of glycosylation at S186 (P = 0.0718);.;.;.;Loss of glycosylation at S186 (P = 0.0718);.;Loss of glycosylation at S186 (P = 0.0718);.;.;.;
MVP		0.96
MPC		0.66
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.96
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs386833730; hg19: chr16-28497785;