dbSNP rs138037471: CLN5:p.Ala29Ala (chr13-76992185-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006493.4(CLN5):c.87C>G(p.Ala29Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,605,390 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 83 hom., cov: 33)

Exomes 𝑓: 0.032 ( 831 hom. )

Consequence

CLN5
NM_006493.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.426

Publications

3 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, Ambry Genetics, Genomics England PanelApp

CLN5 links:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 13-76992185-C-G is Benign according to our data. Variant chr13-76992185-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.426 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0245 (3726/152270) while in subpopulation AMR AF = 0.0352 (538/15298). AF 95% confidence interval is 0.0334. There are 83 homozygotes in GnomAd4. There are 1818 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 83 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006493.4. 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
	CLN5	NM_006493.4	MANE Select	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 5	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLN5	ENST00000377453.9	TSL:1 MANE Select	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 4	ENSP00000366673.5	O75503
CLN5	ENST00000636183.2	TSL:1	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 4	ENSP00000490181.2	O75503
ENSG00000283208	ENST00000638147.2	TSL:5	c.87C>G	p.Ala29Ala	synonymous	Exon 1 of 5	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3732

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00687

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.0657

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.0701

Gnomad NFE

AF:

0.0346

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0239

AC:

5352

AN:

223732

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.00583

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.0644

Gnomad EAS exome

AF:

0.0000577

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0309

GnomAD4 exome

AF:

0.0316

AC:

45973

AN:

1453120

Hom.:

831

Cov.:

AF XY:

0.0311

AC XY:

22463

AN XY:

722840

show subpopulations

African (AFR)

AF:

0.00511

AC:

170

AN:

33264

American (AMR)

AF:

0.0202

AC:

894

AN:

44300

Ashkenazi Jewish (ASJ)

AF:

0.0648

AC:

1681

AN:

25942

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39588

South Asian (SAS)

AF:

0.00827

AC:

709

AN:

85768

European-Finnish (FIN)

AF:

0.0212

AC:

1058

AN:

49800

Middle Eastern (MID)

AF:

0.0338

AC:

153

AN:

4528

European-Non Finnish (NFE)

AF:

0.0356

AC:

39463

AN:

1109998

Other (OTH)

AF:

0.0308

AC:

1844

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2838

5677

8515

11354

14192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1486

2972

4458

5944

7430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0245

AC:

3726

AN:

152270

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1818

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00685

AC:

285

AN:

41578

American (AMR)

AF:

0.0352

AC:

538

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

228

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00746

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0194

AC:

206

AN:

10616

Middle Eastern (MID)

AF:

0.0616

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0346

AC:

2352

AN:

67996

Other (OTH)

AF:

0.0298

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0331

Hom.:

Bravo

AF:

0.0252

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Neuronal ceroid lipofuscinosis 5 (3)

not provided (2)

Inborn genetic diseases (1)

Neuronal ceroid lipofuscinosis (1)

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.8

(source)

DANN

Benign

0.42

PhyloP100

-0.43

PromoterAI

-0.29

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over