rs780828430

Variant names:

• chr8-74351471-TG-T
• rs780828430
• NM_018972.4:c.310+6delG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_018972.4(GDAP1):​c.310+6delG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00108 in 1,602,702 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: GDAP1 NM_018972.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 6.18

Genes affected

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-74351471-TG-T is Benign according to our data. Variant chr8-74351471-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=5}. Variant chr8-74351471-TG-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.310+6delG		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.310+6delG		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000970 AC: 244 AN: 251448 Hom.: 0 AF XY: 0.000912 AC XY: 124 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00109 AC: 1575 AN: 1450346 Hom.: 1 Cov.: 29 AF XY: 0.00109 AC XY: 790 AN XY: 722374

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00507

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74510

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.000790

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2K Uncertain:1 Benign:1

Aug 12, 2021

Laboratory of Functional Genomics, Research Centre for Medical Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

Splicing variant c.310+6delG in GDAP1 gene could be classified as likely benign variant according to AСMG criteria (PM2, BP4, BS3, PM3). The variant vas observed in 31 y.o. female patient with Charcot-Marie-Tooth disease with axonal type of lession in compound heterozygous state with pathogenic c.715C>T variant. -

Nov 03, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1 Benign:1

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310+6delG intronic variant is located 6 nucleotides after coding exon 2 of the GDAP1 gene. This variant results from a deletion of one nucleotide at position c.310+6. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the supporting evidence, this variant is unlikely to be causative of axonal Charcot-Marie-Tooth disease, type 2K (CMT2K); however, its contribution to the development of the autosomal recessive spectrum of diseases is uncertain. -

Charcot-Marie-Tooth with Vocal Cord Paresis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth, Intermediate Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4A Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GDAP1-related disorder Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs780828430; hg19: chr8-75263706;