15-49239225-A-C

Variant names:

• chr15-49239225-A-C
• rs1388585321
• NM_002044.4:c.362A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002044.4(GALK2):​c.362A>C​(p.His121Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H121L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GALK2 NM_002044.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.68
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALK2	NM_002044.4	c.362A>C	p.His121Pro	missense_variant	Exon 5 of 10	ENST00000560031.6	NP_002035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALK2	ENST00000560031.6	c.362A>C	p.His121Pro	missense_variant	Exon 5 of 10	1	NM_002044.4	ENSP00000453129.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461570 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727110

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111730

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.30	.;T;T;T;T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T
Polyphen		0.38	.;.;B;.;.;.;.
Vest4		0.62
MutPred		0.48		.;.;Gain of methylation at K116 (P = 0.062);.;.;.;.;
MVP		0.94
MPC		0.095
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.90
Mutation Taster		=40/60	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: rs1388585321; hg19: chr15-49531422;