NM_001042432.2:c.1210C>A

Variant names:

• chr16-28477623-G-T
• rs146610181
• NM_001042432.2:c.1210C>A

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.1210C>A​(p.His404Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0018 in 1,613,978 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H404Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 4.25
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009625524).
• BP6: Variant 16-28477623-G-T is Benign according to our data. Variant chr16-28477623-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128775.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00808 (1231/152288) while in subpopulation AFR AF = 0.0258 (1070/41550). AF 95% confidence interval is 0.0245. There are 15 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	NM_001042432.2	MANE Select	c.1210C>A	p.His404Asn	missense	Exon 16 of 16	NP_001035897.1
	CLN3	NM_000086.2		c.1210C>A	p.His404Asn	missense	Exon 15 of 15	NP_000077.1
	CLN3	NM_001286104.2		c.1138C>A	p.His380Asn	missense	Exon 15 of 15	NP_001273033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.1210C>A	p.His404Asn	missense	Exon 16 of 16	ENSP00000490105.1
	CLN3	ENST00000359984.12	TSL:1	c.1210C>A	p.His404Asn	missense	Exon 15 of 15	ENSP00000353073.9
	CLN3	ENST00000565316.6	TSL:1	c.1159C>A	p.His387Asn	missense	Exon 14 of 14	ENSP00000456117.1

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1218 AN: 152170 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00268 AC: 671 AN: 250384 AF XY: 0.00192

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00114 AC: 1668 AN: 1461690 Hom.: 14 Cov.: 31 AF XY: 0.00102 AC XY: 741 AN XY: 727132

African (AFR) AF: 0.0212 AC: 710 AN: 33480

American (AMR) AF: 0.00378 AC: 169 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000401 AC: 446 AN: 1112008

Other (OTH) AF: 0.00298 AC: 180 AN: 60396

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152288 Hom.: 15 Cov.: 33 AF XY: 0.00802 AC XY: 597 AN XY: 74462

African (AFR) AF: 0.0258 AC: 1070 AN: 41550

American (AMR) AF: 0.00661 AC: 101 AN: 15288

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00374 Hom.: 56

Bravo AF: 0.00862

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Oct 22, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:3

Apr 13, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis 3 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jun 24, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Neuronal ceroid lipofuscinosis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift	Benign	0.41	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.62
MVP		0.94
MPC		0.66
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.51
gMVP		0.43
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146610181; hg19: chr16-28488944; COSMIC: COSV104413155; COSMIC: COSV104413155;