NM_001042432.2:c.*99C>T

Variant names:

• chr16-28477417-G-A
• rs113845299
• NM_001042432.2:c.*99C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001042432.2(CLN3):​c.*99C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,536,116 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0081 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: CLN3 NM_001042432.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.08
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-28477417-G-A is Benign according to our data. Variant chr16-28477417-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318712.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0081 (1233/152288) while in subpopulation AFR AF = 0.0258 (1072/41572). AF 95% confidence interval is 0.0245. There are 15 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.*99C>T		3_prime_UTR	Exon 16 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_000086.2		c.*99C>T		3_prime_UTR	Exon 15 of 15	NP_000077.1	Q13286-1
	CLN3	NM_001286104.2		c.*99C>T		3_prime_UTR	Exon 15 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.*99C>T		3_prime_UTR	Exon 16 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.*99C>T		3_prime_UTR	Exon 15 of 15	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000357806.11	TSL:1	c.*99C>T		3_prime_UTR	Exon 12 of 12	ENSP00000350457.7	Q13286-6

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152170 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00114 AC: 1582 AN: 1383828 Hom.: 13 Cov.: 22 AF XY: 0.00102 AC XY: 708 AN XY: 691716

African (AFR) AF: 0.0211 AC: 672 AN: 31806

American (AMR) AF: 0.00375 AC: 166 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 133 AN: 25648

East Asian (EAS) AF: 0.00 AC: 0 AN: 39290

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47620

Middle Eastern (MID) AF: 0.00450 AC: 18 AN: 4002

European-Non Finnish (NFE) AF: 0.000397 AC: 417 AN: 1049624

Other (OTH) AF: 0.00301 AC: 174 AN: 57724

GnomAD4 genome AF: 0.00810 AC: 1233 AN: 152288 Hom.: 15 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74456

African (AFR) AF: 0.0258 AC: 1072 AN: 41572

American (AMR) AF: 0.00660 AC: 101 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68016

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00547 Hom.: 1

Bravo AF: 0.00863

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.38
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs113845299; hg19: chr16-28488738;