rs755313503

Variant names:

• chr16-28487544-G-GAGGGGGTGAGAAGGGA
• rs755313503
• NM_001042432.2:c.375-19_375-4dupTCCCTTCTCACCCCCT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_001042432.2(CLN3):​c.375-19_375-4dupTCCCTTCTCACCCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CLN3 NM_001042432.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.198
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, Ambry Genetics, Orphanet

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 16-28487544-G-GAGGGGGTGAGAAGGGA is Benign according to our data. Variant chr16-28487544-G-GAGGGGGTGAGAAGGGA is described in ClinVar as Likely_benign. ClinVar VariationId is 457952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00025 (38/152092) while in subpopulation AMR AF = 0.00151 (23/15244). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.375-19_375-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	NP_001035897.1	Q13286-1
	CLN3	NM_000086.2		c.375-19_375-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	NP_000077.1	Q13286-1
	CLN3	NM_001286104.2		c.303-19_303-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	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.375-19_375-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.375-19_375-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000565316.6	TSL:1	c.375-19_375-4dupTCCCTTCTCACCCCCT		splice_region intron	N/A	ENSP00000456117.1	Q13286-3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000917 AC: 23 AN: 250874 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1461476 Hom.: 0 Cov.: 30 AF XY: 0.0000949 AC XY: 69 AN XY: 727078

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111730

Other (OTH) AF: 0.000248 AC: 15 AN: 60380

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00151 AC: 23 AN: 15244

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000192 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755313503; hg19: chr16-28498865;