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GeneBe

3-46671984-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_147129.5(ALS2CL):​c.2584G>A​(p.Gly862Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ALS2CL
NM_147129.5 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38
Variant links:
Genes affected
ALS2CL (HGNC:20605): (ALS2 C-terminal like) Enables identical protein binding activity. Acts upstream of or within endosome organization. Predicted to be located in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12180573).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALS2CLNM_147129.5 linkuse as main transcriptc.2584G>A p.Gly862Arg missense_variant 24/26 ENST00000318962.9
ALS2CLNM_001190707.2 linkuse as main transcriptc.2584G>A p.Gly862Arg missense_variant 24/26
ALS2CLNR_033815.3 linkuse as main transcriptn.2932G>A non_coding_transcript_exon_variant 24/26
ALS2CLNR_135622.2 linkuse as main transcriptn.3520G>A non_coding_transcript_exon_variant 23/25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALS2CLENST00000318962.9 linkuse as main transcriptc.2584G>A p.Gly862Arg missense_variant 24/261 NM_147129.5 P1Q60I27-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251258
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135812
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461780
Hom.:
0
Cov.:
35
AF XY:
0.0000289
AC XY:
21
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000234
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

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 GeneticsJan 24, 2023The c.2584G>A (p.G862R) alteration is located in exon 24 (coding exon 23) of the ALS2CL gene. This alteration results from a G to A substitution at nucleotide position 2584, causing the glycine (G) at amino acid position 862 to be replaced by an arginine (R). 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
0.082
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.030
T;T
Eigen
Benign
-0.021
Eigen_PC
Benign
-0.031
FATHMM_MKL
Benign
0.52
D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;N
MutationTaster
Benign
0.93
N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.86
N;N
REVEL
Benign
0.10
Sift
Benign
0.040
D;D
Sift4G
Uncertain
0.037
D;D
Polyphen
1.0
D;D
Vest4
0.30
MutPred
0.40
Gain of glycosylation at Y861 (P = 0.0092);Gain of glycosylation at Y861 (P = 0.0092);
MVP
0.25
MPC
0.16
ClinPred
0.27
T
GERP RS
3.5
Varity_R
0.13
gMVP
0.34

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: rs368356424; hg19: chr3-46713474; API