rs2289511

Variant names:

• chr14-87988566-G-A
• rs2289511
• NM_000153.4:c.196-43C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.196-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,354,320 control chromosomes in the GnomAD database, including 243,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26971 hom., cov: 32)
  • Exomes 𝑓: 0.60 (216676 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.658
• Publications: 20 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-87988566-G-A is Benign according to our data. Variant chr14-87988566-G-A is described in ClinVar as Benign. ClinVar VariationId is 255374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.196-43C>T		intron_variant	Intron 1 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.196-43C>T		intron_variant	Intron 1 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90205 AN: 151872 Hom.: 26963 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.622 AC: 152872 AN: 245826 AF XY: 0.617

Gnomad AFR exome AF: 0.564

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.825

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.599 AC: 719780 AN: 1202330 Hom.: 216676 Cov.: 18 AF XY: 0.598 AC XY: 366070 AN XY: 611976

African (AFR) AF: 0.564 AC: 15943 AN: 28284

American (AMR) AF: 0.718 AC: 31856 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 14492 AN: 24506

East Asian (EAS) AF: 0.803 AC: 30924 AN: 38490

South Asian (SAS) AF: 0.599 AC: 48514 AN: 80932

European-Finnish (FIN) AF: 0.571 AC: 30248 AN: 53000

Middle Eastern (MID) AF: 0.607 AC: 3192 AN: 5258

European-Non Finnish (NFE) AF: 0.586 AC: 513505 AN: 875884

Other (OTH) AF: 0.602 AC: 31106 AN: 51630

GnomAD4 genome AF: 0.594 AC: 90249 AN: 151990 Hom.: 26971 Cov.: 32 AF XY: 0.596 AC XY: 44246 AN XY: 74294

African (AFR) AF: 0.565 AC: 23431 AN: 41448

American (AMR) AF: 0.654 AC: 9989 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2029 AN: 3472

East Asian (EAS) AF: 0.814 AC: 4200 AN: 5162

South Asian (SAS) AF: 0.587 AC: 2832 AN: 4826

European-Finnish (FIN) AF: 0.562 AC: 5934 AN: 10554

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.588 AC: 39922 AN: 67946

Other (OTH) AF: 0.585 AC: 1231 AN: 2106

Alfa AF: 0.589 Hom.: 8053

Bravo AF: 0.604

Asia WGS AF: 0.615 AC: 2140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.61
PhyloP100		0.66
Mutation Taster		=99/1	polymorphism (auto)

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: rs2289511; hg19: chr14-88454910;