15-49201245-T-C

Variant names:

• chr15-49201245-T-C
• rs756918705
• NM_002044.4:c.137T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002044.4(GALK2):​c.137T>C​(p.Ile46Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. I46K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALK2 NM_002044.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05
• Publications: 1 publications found

Genes affected

GALK2 (HGNC:4119): (galactokinase 2) This gene encodes a highly efficient N-acetylgalactosamine (GalNAc) kinase, which has galactokinase activity when galactose is present at high concentrations. The encoded protein is a member of the GHMP kinase family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

ENSG00000305168 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALK2	NM_002044.4	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 10	ENST00000560031.6	NP_002035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALK2	ENST00000560031.6	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 10	1	NM_002044.4	ENSP00000453129.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248564 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;D;.;D;D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;.;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		0.97	.;.;D;.;.;.;.;.
Vest4		0.91
MutPred		0.85		.;.;Loss of stability (P = 0.0053);.;.;.;.;.;
MVP		0.99
MPC		0.15
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.90

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: rs756918705; hg19: chr15-49493442;