rs200607029

Variant names:

• chr14-87934749-C-A
• rs200607029
• NM_000153.4:c.2041G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87934749-C-A
• chr14-87934749-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000153.4(GALC):​c.2041G>T​(p.Val681Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V681M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-87934749-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208291.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. 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
	GALC	NM_000153.4	MANE Select	c.2041G>T	p.Val681Leu	missense	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1972G>T	p.Val658Leu	missense	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1963G>T	p.Val655Leu	missense	Exon 17 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.2041G>T	p.Val681Leu	missense	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.2002G>T	p.Val668Leu	missense	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1975G>T	p.Val659Leu	missense	Exon 17 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461042 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726842

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111470

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.041
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.041	B
Vest4		0.21
MutPred		0.60		Loss of sheet (P = 0.007)
MVP		0.88
MPC		0.18
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.089
gMVP		0.84
Mutation Taster		=45/55	disease causing

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: rs200607029; hg19: chr14-88401093;