16-28477623-G-T

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: 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 (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

Sel.	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	Q13286-1
	CLN3	NM_000086.2		c.1210C>A	p.His404Asn	missense	Exon 15 of 15	NP_000077.1	Q13286-1
	CLN3	NM_001286104.2		c.1138C>A	p.His380Asn	missense	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.1210C>A	p.His404Asn	missense	Exon 16 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.1210C>A	p.His404Asn	missense	Exon 15 of 15	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000565316.6	TSL:1	c.1159C>A	p.His387Asn	missense	Exon 14 of 14	ENSP00000456117.1	Q13286-3

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Neuronal ceroid lipofuscinosis 3 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	1	-	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

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;