8-19405920-G-C

Variant names:

• chr8-19405920-G-C
• NM_001354483.2:c.1459C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001354483.2(CSGALNACT1):​c.1459C>G​(p.Pro487Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CSGALNACT1 NM_001354483.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

Genes affected

CSGALNACT1 (HGNC:24290): (chondroitin sulfate N-acetylgalactosaminyltransferase 1) This gene encodes an enzyme that transfers N-acetylglucosamine (GalNAc) to the core tetrasaccharide linker and to elongating chondroitin sulfate chains in proteoglycans. Knockout of the orthologous mouse gene indicates that the protein is necessary for normal cartilage development and aggrecan metabolism. Mutations in this gene are associated with multiple sclerosis progression, and with mild skeletal dysplasia and joint laxity. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSGALNACT1	NM_001354483.2	c.1459C>G	p.Pro487Ala	missense_variant	Exon 9 of 9	ENST00000692225.2	NP_001341412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSGALNACT1	ENST00000692225.2	c.1459C>G	p.Pro487Ala	missense_variant	Exon 9 of 9		NM_001354483.2	ENSP00000509853.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1459C>G (p.P487A) alteration is located in exon 10 (coding exon 7) of the CSGALNACT1 gene. This alteration results from a C to G substitution at nucleotide position 1459, causing the proline (P) at amino acid position 487 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;.;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.88	P;P;P
Vest4		0.57
MutPred		0.49		Loss of catalytic residue at P487 (P = 0.0556);Loss of catalytic residue at P487 (P = 0.0556);Loss of catalytic residue at P487 (P = 0.0556);
MVP		0.32
MPC		0.12
ClinPred		0.80	D
GERP RS		5.9
Varity_R		0.14
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-19263431;