Variant 3-46674704-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_147129.5(ALS2CL):c.2291T>A(p.Met764Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALS2CL
NM_147129.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00

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:

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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
ALS2CL	NM_147129.5 linkuse as main transcript	c.2291T>A	p.Met764Lys	missense_variant	21/26	ENST00000318962.9
ALS2CL	NM_001190707.2 linkuse as main transcript	c.2291T>A	p.Met764Lys	missense_variant	21/26
ALS2CL	NR_033815.3 linkuse as main transcript	n.2639T>A		non_coding_transcript_exon_variant	21/26
ALS2CL	NR_135622.2 linkuse as main transcript	n.3227T>A		non_coding_transcript_exon_variant	20/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2CL	ENST00000318962.9 linkuse as main transcript	c.2291T>A	p.Met764Lys	missense_variant	21/26	1	NM_147129.5	P1	Q60I27-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 02, 2021

The c.2291T>A (p.M764K) alteration is located in exon 21 (coding exon 20) of the ALS2CL gene. This alteration results from a T to A substitution at nucleotide position 2291, causing the methionine (M) at amino acid position 764 to be replaced by a lysine (K). 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.025

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.0053

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.94

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.14

B;B

Vest4

0.58

MutPred

0.69

Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);

MVP

0.26

MPC

0.20

ClinPred

0.85

GERP RS

5.5

Varity_R

0.74

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over