ENST00000636228.1:c.-39G>A

Variant names:

• chr16-28491715-C-T
• rs201824641
• ENST00000636228.1:c.-39G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000636228.1(CLN3):​c.-39G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,614,092 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (19 hom.)
• Consequence: CLN3 ENST00000636228.1 splice_region
• Scores: Splicing: ADA: 0.0001488
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0740
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 16-28491715-C-T is Benign according to our data. Variant chr16-28491715-C-T is described in ClinVar as Benign. ClinVar VariationId is 136783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000807 (123/152364) while in subpopulation SAS AF = 0.0133 (64/4830). AF 95% confidence interval is 0.0106. There are 1 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636228.1. 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.45G>A	p.Glu15Glu	splice_region synonymous	Exon 2 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_001286110.2		c.-39G>A		splice_region	Exon 1 of 14	NP_001273039.1	B4DFF3
	CLN3	NM_001286109.2		c.-39G>A		splice_region	Exon 1 of 14	NP_001273038.1	Q2TA70

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636228.1	TSL:1	c.-39G>A		splice_region	Exon 1 of 13	ENSP00000489627.1	O95086
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.45G>A	p.Glu15Glu	splice_region synonymous	Exon 2 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.45G>A	p.Glu15Glu	splice_region synonymous	Exon 1 of 15	ENSP00000353073.9	Q13286-1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00235 AC: 588 AN: 250112 AF XY: 0.00287

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00730

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000926 AC: 1354 AN: 1461728 Hom.: 19 Cov.: 31 AF XY: 0.00128 AC XY: 931 AN XY: 727164

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00338 AC: 134 AN: 39676

South Asian (SAS) AF: 0.0124 AC: 1073 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5748

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111962

Other (OTH) AF: 0.00197 AC: 119 AN: 60390

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74510

African (AFR) AF: 0.0000481 AC: 2 AN: 41596

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5182

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000393

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal ceroid lipofuscinosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		-0.074
PromoterAI		-0.066	Neutral
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.032
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: rs201824641; hg19: chr16-28503036;