rs150986176

Variant names:

• chr16-28482128-T-A
• rs150986176
• NM_001042432.2:c.1033A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-28482128-T-A
• chr16-28482128-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001042432.2(CLN3):​c.1033A>T​(p.Thr345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T345T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.14
• Publications: 3 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: Ambry Genetics, Genomics England PanelApp, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001042432.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3650626).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042432.2. 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
	CLN3	NM_001042432.2	MANE Select	c.1033A>T	p.Thr345Ser	missense	Exon 14 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_000086.2		c.1033A>T	p.Thr345Ser	missense	Exon 13 of 15	NP_000077.1	Q13286-1
	CLN3	NM_001286104.2		c.961A>T	p.Thr321Ser	missense	Exon 13 of 15	NP_001273033.1	Q13286-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.1033A>T	p.Thr345Ser	missense	Exon 14 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.1033A>T	p.Thr345Ser	missense	Exon 13 of 15	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000565316.6	TSL:1	c.982A>T	p.Thr328Ser	missense	Exon 12 of 14	ENSP00000456117.1	Q13286-3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151632 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248462 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461214 Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111854

Other (OTH) AF: 0.000116 AC: 7 AN: 60368

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151632 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74040

African (AFR) AF: 0.00 AC: 0 AN: 41206

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Neuronal ceroid lipofuscinosis 3 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuronal ceroid lipofuscinosis (1)
-	1	-	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.85	P
Vest4		0.52
MutPred		0.39		Gain of MoRF binding (P = 0.1205)
MVP		0.70
MPC		0.34
ClinPred		0.60	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.30
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150986176; hg19: chr16-28493449;