chr8-74362940-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong

The NM_018972.4(GDAP1):c.581C>G(p.Ser194*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000494 in 1,418,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S194S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

GDAP1
NM_018972.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9858

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 7.31

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2K
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Charcot-Marie-Tooth disease recessive intermediate A
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant Charcot-Marie-Tooth disease type 2K
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 4A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GDAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 8-74362940-C-G is Pathogenic according to our data. Variant chr8-74362940-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDAP1	NM_018972.4	MANE Select	c.581C>G	p.Ser194*	stop_gained splice_region	Exon 5 of 6	NP_061845.2	Q8TB36-1
GDAP1	NM_001362930.2		c.407C>G	p.Ser136*	stop_gained splice_region	Exon 4 of 5	NP_001349859.1	A0A6Q8PEZ4
GDAP1	NM_001040875.4		c.377C>G	p.Ser126*	stop_gained splice_region	Exon 5 of 6	NP_001035808.1	Q8TB36-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.581C>G	p.Ser194*	stop_gained splice_region	Exon 5 of 6	ENSP00000220822.7	Q8TB36-1
GDAP1	ENST00000434412.3	TSL:1	c.449C>G	p.Ser150*	stop_gained splice_region	Exon 6 of 7	ENSP00000417006.3	A0A7I2RYU0
GDAP1	ENST00000675463.1		c.581C>G	p.Ser194*	stop_gained splice_region	Exon 5 of 7	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251230

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000316

AC:

AN:

1266574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

640844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29748

American (AMR)

AF:

0.0000674

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24972

East Asian (EAS)

AF:

0.00

AC:

AN:

38726

South Asian (SAS)

AF:

0.00

AC:

AN:

82350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

934036

Other (OTH)

AF:

0.0000186

AC:

AN:

53790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151820

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41286

American (AMR)

AF:

0.000131

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4A (5)

Charcot-Marie-Tooth disease axonal type 2K (2)

Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1843183:Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive;C1859198:Charcot-Marie-Tooth disease type 4A (1)

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

PhyloP100

7.3

Vest4

0.71

GERP RS

4.5

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.89

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over