Genetic Variant GALC:c.1834+21_1834+22dupTT (chr14-87941372-T-TAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000153.4(GALC):c.1834+21_1834+22dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 0)

Exomes 𝑓: 0.027 ( 7 hom. )

Consequence

GALC
NM_000153.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.263

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.1834+21_1834+22dupTT		intron_variant	Intron 15 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.1834+22_1834+23insTT		intron_variant	Intron 15 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

351

AN:

146902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00622

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00115

Gnomad ASJ

AF:

0.00466

Gnomad EAS

AF:

0.00240

Gnomad SAS

AF:

0.000856

Gnomad FIN

AF:

0.000744

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000690

Gnomad OTH

AF:

0.00100

GnomAD2 exomes

AF:

0.0245

AC:

4109

AN:

167536

AF XY:

0.0242

show subpopulations

Gnomad AFR exome

AF:

0.0135

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.0464

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0270

AC:

29834

AN:

1103342

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

14908

AN XY:

558636

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0125

AC:

316

AN:

25236

American (AMR)

AF:

0.0298

AC:

1065

AN:

35744

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

567

AN:

21540

East Asian (EAS)

AF:

0.0523

AC:

1702

AN:

32522

South Asian (SAS)

AF:

0.0263

AC:

1874

AN:

71154

European-Finnish (FIN)

AF:

0.0209

AC:

865

AN:

41420

Middle Eastern (MID)

AF:

0.0210

AC:

AN:

4676

European-Non Finnish (NFE)

AF:

0.0268

AC:

22050

AN:

824090

Other (OTH)

AF:

0.0276

AC:

1297

AN:

46960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

2830

5661

8491

11322

14152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.00243

AC:

357

AN:

146950

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

180

AN XY:

71292

show subpopulations

African (AFR)

AF:

0.00631

AC:

251

AN:

39808

American (AMR)

AF:

0.00122

AC:

AN:

14760

Ashkenazi Jewish (ASJ)

AF:

0.00466

AC:

AN:

3430

East Asian (EAS)

AF:

0.00240

AC:

AN:

4996

South Asian (SAS)

AF:

0.000859

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.000744

AC:

AN:

9412

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000690

AC:

AN:

66690

Other (OTH)

AF:

0.000994

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0174

Hom.:

978

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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14-87941372-TAAA-TAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over