Variant 3-46676321-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_147129.5(ALS2CL):c.2110G>A(p.Gly704Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ALS2CL
NM_147129.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.64

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]

ALS2CL links:

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=0.2534304).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALS2CL	NM_147129.5 linkuse as main transcript	c.2110G>A	p.Gly704Arg	missense_variant	19/26	ENST00000318962.9
ALS2CL	NM_001190707.2 linkuse as main transcript	c.2110G>A	p.Gly704Arg	missense_variant	19/26
ALS2CL	NR_033815.3 linkuse as main transcript	n.2168G>A		non_coding_transcript_exon_variant	19/26
ALS2CL	NR_135622.2 linkuse as main transcript	n.2168G>A		non_coding_transcript_exon_variant	19/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2CL	ENST00000318962.9 linkuse as main transcript	c.2110G>A	p.Gly704Arg	missense_variant	19/26	1	NM_147129.5	P1	Q60I27-1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251366

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135868

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:

0.00137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727158

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:

0.00130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000534

Hom.:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.2110G>A (p.G704R) alteration is located in exon 19 (coding exon 18) of the ALS2CL gene. This alteration results from a G to A substitution at nucleotide position 2110, causing the glycine (G) at amino acid position 704 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

0.32

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.047

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.35

Sift

Benign

0.098

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.49

Gain of MoRF binding (P = 0.0051);Gain of MoRF binding (P = 0.0051);

MVP

0.32

MPC

0.61

ClinPred

0.44

GERP RS

4.8

Varity_R

0.38

gMVP

0.58

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.

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