19-35295965-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002361.4(MAG):​c.399C>G​(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. Variant has been reported in ClinVar as Pathogenic (no stars). 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: Pathogenic no assertion criteria provided P:1
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35295965-C-G is Pathogenic according to our data. Variant chr19-35295965-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 218187.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 75 Pathogenic:1

Sep 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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	0.0	.;T;.;.;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.85	T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.45	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	0.0	.;N;N;.;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;T;.;D
Sift4G	Benign	0.12	T;T;T;T;T
Vest4		0.0
ClinPred		0.45	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.78
Mutation Taster		=12/88	disease causing (ClinVar)

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;