13-76992204-G-C

Variant names:

• chr13-76992204-G-C
• rs778982551
• NM_006493.4:c.106G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000377453.9(CLN5):​c.106G>C​(p.Ala36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,603,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. A36V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (1 hom.)
• Consequence: CLN5 ENST00000377453.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.706
• Publications: 0 publications found

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

CLN5 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ENSG00000283208 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14738536).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000377453.9. 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
	CLN5	NM_006493.4	MANE Select	c.106G>C	p.Ala36Pro	missense	Exon 1 of 4	NP_006484.2
	CLN5	NM_001366624.2		c.106G>C	p.Ala36Pro	missense	Exon 1 of 5	NP_001353553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.106G>C	p.Ala36Pro	missense	Exon 1 of 4	ENSP00000366673.5
	CLN5	ENST00000636183.2	TSL:1	c.106G>C	p.Ala36Pro	missense	Exon 1 of 4	ENSP00000490181.2
	ENSG00000283208	ENST00000638147.2	TSL:5	c.106G>C	p.Ala36Pro	missense	Exon 1 of 5	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000908 AC: 20 AN: 220342 AF XY: 0.0000657

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1450834 Hom.: 1 Cov.: 35 AF XY: 0.0000152 AC XY: 11 AN XY: 721740

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.000521 AC: 23 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4362

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109782

Other (OTH) AF: 0.0000167 AC: 1 AN: 59874

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Neuronal ceroid lipofuscinosis 5 (2)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.71
PrimateAI	Uncertain	0.70	T
REVEL	Benign	0.21
Polyphen		0.98	D
MutPred		0.49		Loss of helix (P = 0.0017)
MVP		0.52
MPC		0.75
ClinPred		0.13	T
GERP RS		-2.1
PromoterAI		-0.045	Neutral
Varity_R		0.26
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs778982551; hg19: chr13-77566339;