NM_001042432.2:c.*155A>C

Variant names:

• chr16-28477361-T-G
• rs113112766
• NM_001042432.2:c.*155A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042432.2(CLN3):​c.*155A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 990,702 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (11 hom.)
• Consequence: CLN3 NM_001042432.2 3_prime_UTR
• Scores: Splicing: ADA: 0.00003789
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.28
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-28477361-T-G is Benign according to our data. Variant chr16-28477361-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 318711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1540/152266) while in subpopulation AFR AF = 0.0356 (1479/41570). AF 95% confidence interval is 0.0341. There are 23 homozygotes in GnomAd4. There are 748 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.*155A>C		3_prime_UTR_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.*155A>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_001042432.2	ENSP00000490105.1
ENSG00000261832	ENST00000637378.1	c.228+4744A>C		intron_variant	Intron 4 of 9	5		ENSP00000490831.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1530 AN: 152148 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00117 AC: 978 AN: 838436 Hom.: 11 Cov.: 11 AF XY: 0.000930 AC XY: 400 AN XY: 430104

African (AFR) AF: 0.0353 AC: 740 AN: 20968

American (AMR) AF: 0.00181 AC: 62 AN: 34178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20876

East Asian (EAS) AF: 0.00 AC: 0 AN: 33644

South Asian (SAS) AF: 0.0000589 AC: 4 AN: 67948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35080

Middle Eastern (MID) AF: 0.00276 AC: 8 AN: 2902

European-Non Finnish (NFE) AF: 0.0000737 AC: 43 AN: 583252

Other (OTH) AF: 0.00306 AC: 121 AN: 39588

GnomAD4 genome AF: 0.0101 AC: 1540 AN: 152266 Hom.: 23 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74456

African (AFR) AF: 0.0356 AC: 1479 AN: 41570

American (AMR) AF: 0.00248 AC: 38 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67994

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.0127 Hom.: 21

Bravo AF: 0.0120

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neuronal ceroid lipofuscinosis 3 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.7
DANN	Benign	0.52
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
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: rs113112766; hg19: chr16-28488682;