chr15-51341922-T-C

Position:

• chr15-51341922-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181789.4(GLDN):​c.238T>C​(p.Ser80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,443,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: GLDN NM_181789.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.865

Genes affected

GLDN (HGNC:29514): (gliomedin) This gene encodes a protein that contains olfactomedin-like and collagen-like domains. The encoded protein, which exists in both transmembrane and secreted forms, promotes formation of the nodes of Ranvier in the peripheral nervous system. Mutations in this gene cause a form of lethal congenital contracture syndrome in human patients. Autoantibodies to the encoded protein have been identified in sera form patients with multifocal motor neuropathy. [provided by RefSeq, May 2017]

GLDN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044743508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDN	NM_181789.4	c.238T>C	p.Ser80Pro	missense_variant	1/10	ENST00000335449.11	NP_861454.2
GLDN	XM_017022121.2	c.238T>C	p.Ser80Pro	missense_variant	1/9		XP_016877610.1
GLDN	XM_017022125.1	c.238T>C	p.Ser80Pro	missense_variant	1/10		XP_016877614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDN	ENST00000335449.11	c.238T>C	p.Ser80Pro	missense_variant	1/10	2	NM_181789.4	ENSP00000335196.6
GLDN	ENST00000558286.5	n.49T>C		non_coding_transcript_exon_variant	1/3	1
GLDN	ENST00000560215.5	c.124T>C	p.Ser42Pro	missense_variant	1/4	4		ENSP00000484633.1
GLDN	ENST00000560690.5	n.-24T>C		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1443118 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718224

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000998

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

Asia WGS AF: 0.00405 AC: 14 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.1
DANN	Benign	0.30
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Loss of phosphorylation at S80 (P = 0.0018);
MVP		0.21
MPC		0.14
ClinPred		0.014	T
GERP RS		1.6
Varity_R		0.058
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs955650651; hg19: chr15-51634119;