16-28477548-G-T

Variant names:

• chr16-28477548-G-T
• rs1433950864
• NM_001042432.2:c.1285C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001042432.2(CLN3):​c.1285C>A​(p.Pro429Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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]

ENSG00000261832 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.1285C>A	p.Pro429Thr	missense_variant	Exon 16 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.1285C>A	p.Pro429Thr	missense_variant	Exon 16 of 16	1	NM_001042432.2	ENSP00000490105.1
ENSG00000261832	ENST00000637378.1	c.228+4557C>A		intron_variant	Intron 4 of 9	5		ENSP00000490831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;D;.;.;D;D;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;M;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.3	.;D;.;.;D;D;D;.;D;.;D;.;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	.;D;.;.;D;D;D;.;D;.;D;.;.;D
Sift4G	Pathogenic	0.0	.;.;D;.;D;D;D;.;D;.;D;.;.;.
Polyphen		1.0	D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4		0.61, 0.71, 0.71, 0.69, 0.69, 0.78
MutPred		0.81		Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);.;.;.;.;.;.;Loss of stability (P = 0.0445);.;.;.;.;.;
MVP		0.96
MPC		0.67
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1433950864; hg19: chr16-28488869;