rs2301600

Variant names:

• chr19-35295965-C-A
• rs2301600
• NM_002361.4:c.399C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35295965-C-A
• chr19-35295965-C-G
• chr19-35295965-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PM2

The NM_002361.4(MAG):​c.399C>A​(p.Ser133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S133S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 33 publications found

Genes affected

MAG (HGNC:6783): (myelin associated glycoprotein) The protein encoded by this gene is a type I membrane protein and member of the immunoglobulin superfamily. It is thought to be involved in the process of myelination. It is a lectin that binds to sialylated glycoconjugates and mediates certain myelin-neuron cell-cell interactions. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2010]

MAG Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 75

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• PS1: Transcript NM_002361.4 (MAG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.399C>A	p.Ser133Arg	missense_variant	Exon 4 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.324C>A	p.Ser108Arg	missense_variant	Exon 4 of 11		NP_001186145.1
MAG	NM_080600.3	c.399C>A	p.Ser133Arg	missense_variant	Exon 4 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.399C>A	p.Ser133Arg	missense_variant	Exon 4 of 11	1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;.;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	.;N;N;.;.
PhyloP100		0.37
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.88	.;N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.11	.;T;T;.;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.99	.;D;.;.;.
Vest4		0.65, 0.66, 0.63
MutPred		0.52		.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		0.74
MPC		0.62
ClinPred		0.38	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.78
Mutation Taster		=12/88	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: rs2301600; hg19: chr19-35786868;