19-35295965-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002361.4(MAG):​c.399C>T​(p.Ser133Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,590,544 control chromosomes in the GnomAD database, including 48,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3910 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44328 hom.)
• Consequence: MAG NM_002361.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-35295965-C-T is Benign according to our data. Variant chr19-35295965-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.368 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.399C>T	p.Ser133Ser	synonymous_variant	Exon 4 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 4 of 11		NP_001186145.1
MAG	NM_080600.3	c.399C>T	p.Ser133Ser	synonymous_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>T	p.Ser133Ser	synonymous_variant	Exon 4 of 11	1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32357 AN: 152038 Hom.: 3901 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.274 AC: 63903 AN: 233174 AF XY: 0.274

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.410

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.242 AC: 347399 AN: 1438388 Hom.: 44328 Cov.: 34 AF XY: 0.245 AC XY: 174693 AN XY: 712896

African (AFR) AF: 0.120 AC: 3927 AN: 32752

American (AMR) AF: 0.381 AC: 16090 AN: 42198

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5616 AN: 24606

East Asian (EAS) AF: 0.422 AC: 16650 AN: 39420

South Asian (SAS) AF: 0.356 AC: 29715 AN: 83364

European-Finnish (FIN) AF: 0.219 AC: 11487 AN: 52400

Middle Eastern (MID) AF: 0.226 AC: 1277 AN: 5646

European-Non Finnish (NFE) AF: 0.226 AC: 247976 AN: 1098720

Other (OTH) AF: 0.247 AC: 14661 AN: 59282

GnomAD4 genome AF: 0.213 AC: 32398 AN: 152156 Hom.: 3910 Cov.: 32 AF XY: 0.219 AC XY: 16286 AN XY: 74356

African (AFR) AF: 0.123 AC: 5120 AN: 41548

American (AMR) AF: 0.308 AC: 4710 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3472

East Asian (EAS) AF: 0.413 AC: 2133 AN: 5166

South Asian (SAS) AF: 0.363 AC: 1753 AN: 4828

European-Finnish (FIN) AF: 0.220 AC: 2323 AN: 10566

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14898 AN: 67980

Other (OTH) AF: 0.211 AC: 444 AN: 2106

Alfa AF: 0.222 Hom.: 7389

Bravo AF: 0.213

Asia WGS AF: 0.373 AC: 1300 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 75 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV62701232;