NM_001042432.2:c.222T>C

Variant names:

• chr16-28489290-A-G
• rs201225986
• NM_001042432.2:c.222T>C
• CLN3 p.His74His

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6 BP7

The NM_001042432.2(CLN3):​c.222T>C​(p.His74His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,607,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CLN3 NM_001042432.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002566
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: -0.682
• Publications: 6 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, Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-28489290-A-G is Benign according to our data. Variant chr16-28489290-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457951.
• BP7: Synonymous conserved (PhyloP=-0.682 with no splicing effect.

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.222T>C	p.His74His	splice_region synonymous	Exon 4 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_001286105.2		c.2T>C	p.Met1?	start_lost splice_region	Exon 2 of 13	NP_001273034.1	B4DMY6
	CLN3	NM_000086.2		c.222T>C	p.His74His	splice_region synonymous	Exon 3 of 15	NP_000077.1	Q13286-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.222T>C	p.His74His	splice_region synonymous	Exon 4 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.222T>C	p.His74His	splice_region synonymous	Exon 3 of 15	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000565316.6	TSL:1	c.222T>C	p.His74His	splice_region synonymous	Exon 3 of 14	ENSP00000456117.1	Q13286-3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000685 AC: 17 AN: 248016 AF XY: 0.0000597

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.0000891

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000107 AC: 155 AN: 1455380 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 74 AN XY: 724126

African (AFR) AF: 0.0000899 AC: 3 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85634

European-Finnish (FIN) AF: 0.000413 AC: 22 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1107024

Other (OTH) AF: 0.000166 AC: 10 AN: 60190

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

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

Alfa AF: 0.000117 Hom.: 1

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	Neuronal ceroid lipofuscinosis (2)
-	2	-	Neuronal ceroid lipofuscinosis 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	0.58
DANN	Benign	0.72
PhyloP100		-0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.090
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201225986;

hg19: chr16-28500611;