chr1-117887766-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017686.4(GDAP2):​c.962G>A​(p.Arg321His) variant causes a missense change. The variant allele was found at a frequency of 0.0000202 in 1,535,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GDAP2
NM_017686.4 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02
Variant links:
Genes affected
GDAP2 (HGNC:18010): (ganglioside induced differentiation associated protein 2) Predicted to act upstream of or within response to retinoic acid. Located in lysosomal membrane. Implicated in autosomal recessive spinocerebellar ataxia 27. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GDAP2NM_017686.4 linkuse as main transcriptc.962G>A p.Arg321His missense_variant 9/14 ENST00000369443.10 NP_060156.1
GDAP2NM_001135589.3 linkuse as main transcriptc.962G>A p.Arg321His missense_variant 9/13 NP_001129061.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GDAP2ENST00000369443.10 linkuse as main transcriptc.962G>A p.Arg321His missense_variant 9/142 NM_017686.4 ENSP00000358451 P1Q9NXN4-1
GDAP2ENST00000369442.3 linkuse as main transcriptc.962G>A p.Arg321His missense_variant 9/131 ENSP00000358450 Q9NXN4-2
GDAP2ENST00000464026.1 linkuse as main transcriptn.240G>A non_coding_transcript_exon_variant 3/52
GDAP2ENST00000491626.5 linkuse as main transcript upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151828
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000480
AC:
12
AN:
249992
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135188
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000545
Gnomad SAS exome
AF:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000195
AC:
27
AN:
1384116
Hom.:
0
Cov.:
23
AF XY:
0.0000188
AC XY:
13
AN XY:
693046
show subpopulations
Gnomad4 AFR exome
AF:
0.0000314
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000255
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000134
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
151828
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74106
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 13, 2021The c.962G>A (p.R321H) alteration is located in exon 9 (coding exon 8) of the GDAP2 gene. This alteration results from a G to A substitution at nucleotide position 962, causing the arginine (R) at amino acid position 321 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.29
T;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.060
D
MetaRNN
Uncertain
0.70
D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-3.9
D;D
REVEL
Uncertain
0.46
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.42
Loss of MoRF binding (P = 0.0077);Loss of MoRF binding (P = 0.0077);
MVP
0.74
MPC
0.84
ClinPred
0.83
D
GERP RS
5.5
Varity_R
0.59
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs370788372; hg19: chr1-118430388; COSMIC: COSV105924506; COSMIC: COSV105924506; API