rs1805078

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):c.550C>T(p.Arg184Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,612,988 control chromosomes in the GnomAD database, including 2,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 175 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2247 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:8O:2

Conservation

PhyloP100: 2.62

Publications

40 publications found

Variant links:

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

GALC Gene-Disease associations (from GenCC):

Krabbe disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

GALC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072863996).

BP6

Variant 14-87984426-G-A is Benign according to our data. Variant chr14-87984426-G-A is described in ClinVar as Benign|other. ClinVar VariationId is 92506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.550C>T	p.Arg184Cys	missense_variant	Exon 5 of 17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.550C>T	p.Arg184Cys	missense_variant	Exon 5 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5900

AN:

151994

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0495

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00578

Gnomad SAS

AF:

0.0346

Gnomad FIN

AF:

0.0706

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0565

Gnomad OTH

AF:

0.0355

GnomAD2 exomes

AF:

0.0417

AC:

10401

AN:

249442

AF XY:

0.0428

show subpopulations

Gnomad AFR exome

AF:

0.00982

Gnomad AMR exome

AF:

0.0203

Gnomad ASJ exome

AF:

0.0139

Gnomad EAS exome

AF:

0.00200

Gnomad FIN exome

AF:

0.0693

Gnomad NFE exome

AF:

0.0570

Gnomad OTH exome

AF:

0.0423

GnomAD4 exome

AF:

0.0523

AC:

76449

AN:

1460876

Hom.:

2247

Cov.:

AF XY:

0.0520

AC XY:

37819

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.00786

AC:

263

AN:

33478

American (AMR)

AF:

0.0213

AC:

953

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

356

AN:

26132

East Asian (EAS)

AF:

0.0112

AC:

446

AN:

39688

South Asian (SAS)

AF:

0.0366

AC:

3153

AN:

86240

European-Finnish (FIN)

AF:

0.0689

AC:

3679

AN:

53402

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5768

European-Non Finnish (NFE)

AF:

0.0582

AC:

64626

AN:

1111082

Other (OTH)

AF:

0.0468

AC:

2825

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

3285

6569

9854

13138

16423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2326

4652

6978

9304

11630

<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:

0.0388

AC:

5896

AN:

152112

Hom.:

175

Cov.:

AF XY:

0.0379

AC XY:

2819

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0111

AC:

459

AN:

41504

American (AMR)

AF:

0.0315

AC:

481

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3470

East Asian (EAS)

AF:

0.00579

AC:

AN:

5178

South Asian (SAS)

AF:

0.0347

AC:

167

AN:

4816

European-Finnish (FIN)

AF:

0.0706

AC:

746

AN:

10568

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0565

AC:

3840

AN:

67988

Other (OTH)

AF:

0.0346

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

280

561

841

1122

1402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0483

Hom.:

780

Bravo

AF:

0.0336

TwinsUK

AF:

0.0591

AC:

219

ALSPAC

AF:

0.0618

AC:

238

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.0561

AC:

463

ExAC

AF:

0.0431

AC:

5212

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0526

EpiControl

AF:

0.0498

ClinVar

Significance: Benign; other

Submissions summary: Benign:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Galactosylceramide beta-galactosidase deficiency

Benign:2Other:2

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Jan 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- pseudodeficiency allele

not provided

Benign:2

Jan 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32661301, 26865610, 26795590, 7581365, 21228398, 20981092, 22995991) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0073

T;T;T;T

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.5

L;.;.;.

PhyloP100

2.6

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.99

D;P;D;.

Vest4

0.14

MPC

0.43

ClinPred

0.029

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.68

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over