Variant 8-74351471-TG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 6.18

Variant links:

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]

GDAP1 links:

GDAP1 (HGNC:):

GDAP1 links:

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ACMG classification

Classification made for transcript

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, Uncertain_significance=5, Benign=1}. Variant chr8-74351471-TG-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1	NM_018972.4 linkuse as main transcript	c.310+6delG		splice_region_variant, intron_variant		ENST00000220822.12	NP_061845.2	Q8TB36-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12 linkuse as main transcript	c.310+6delG		splice_region_variant, intron_variant		1	NM_018972.4	ENSP00000220822.7		Q8TB36-1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152238

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000912

AC XY:

124

AN XY:

135900

show subpopulations

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.:

Cov.:

AF XY:

0.00109

AC XY:

790

AN XY:

722374

show subpopulations

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.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74510

show subpopulations

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.:

Bravo

AF:

0.000790

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2K

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 03, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing;in vitro	Laboratory of Functional Genomics, Research Centre for Medical Genetics	Aug 12, 2021	Splicing variant c.310+6delG in GDAP1 gene could be classified as likely benign variant according to AÐ¡MG 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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charcot-Marie-Tooth, Intermediate

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

GDAP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over