NM_001354483.2:c.1562G>C

Variant names:

• chr8-19405817-C-G
• rs61910741
• NM_001354483.2:c.1562G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001354483.2(CSGALNACT1):​c.1562G>C​(p.Arg521Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0053 in 1,614,096 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (32 hom.)
• Consequence: CSGALNACT1 NM_001354483.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.71
• Publications: 9 publications found

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]

CSGALNACT1 Gene-Disease associations (from GenCC):

• skeletal dysplasia, mild, with joint laxity and advanced bone age

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078080297).
• BP6: Variant 8-19405817-C-G is Benign according to our data. Variant chr8-19405817-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1599898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00369 (561/152214) while in subpopulation NFE AF = 0.00618 (420/68006). AF 95% confidence interval is 0.00569. There are 4 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354483.2. 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
	CSGALNACT1	NM_001354483.2	MANE Select	c.1562G>C	p.Arg521Pro	missense	Exon 9 of 9	NP_001341412.1	Q8TDX6-1
	CSGALNACT1	NM_001130518.2		c.1562G>C	p.Arg521Pro	missense	Exon 10 of 10	NP_001123990.1	Q8TDX6-1
	CSGALNACT1	NM_001354475.2		c.1562G>C	p.Arg521Pro	missense	Exon 10 of 10	NP_001341404.1	Q8TDX6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSGALNACT1	ENST00000692225.2	MANE Select	c.1562G>C	p.Arg521Pro	missense	Exon 9 of 9	ENSP00000509853.1	Q8TDX6-1
	CSGALNACT1	ENST00000332246.10	TSL:1	c.1562G>C	p.Arg521Pro	missense	Exon 10 of 10	ENSP00000330805.6	Q8TDX6-1
	CSGALNACT1	ENST00000454498.6	TSL:1	c.1562G>C	p.Arg521Pro	missense	Exon 10 of 10	ENSP00000411816.2	Q8TDX6-1

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 561 AN: 152096 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00618

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00388 AC: 976 AN: 251434 AF XY: 0.00395

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00547 AC: 8000 AN: 1461882 Hom.: 32 Cov.: 31 AF XY: 0.00533 AC XY: 3873 AN XY: 727244

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00735 AC: 192 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86258

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53410

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00651 AC: 7235 AN: 1112010

Other (OTH) AF: 0.00391 AC: 236 AN: 60396

GnomAD4 genome AF: 0.00369 AC: 561 AN: 152214 Hom.: 4 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74414

African (AFR) AF: 0.00104 AC: 43 AN: 41544

American (AMR) AF: 0.00268 AC: 41 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00618 AC: 420 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00516 Hom.: 2

Bravo AF: 0.00359

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CSGALNACT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.44
MPC		0.15
ClinPred		0.025	T
GERP RS		5.9
Varity_R		0.64
gMVP		0.72
Mutation Taster		=100/0	polymorphism

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: rs61910741; hg19: chr8-19263328; COSMIC: COSV59979044;