rs554056115

Variant names:

• chr3-46675660-C-T
• rs554056115
• NM_147129.5:c.2213G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-46675660-C-T
• chr3-46675660-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_147129.5(ALS2CL):​c.2213G>A​(p.Arg738His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R738C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: ALS2CL NM_147129.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.341
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02402234).
• BS2: High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2CL	NM_147129.5	MANE Select	c.2213G>A	p.Arg738His	missense	Exon 20 of 26	NP_667340.2
	ALS2CL	NM_001190707.2		c.2213G>A	p.Arg738His	missense	Exon 20 of 26	NP_001177636.1	Q60I27-1
	ALS2CL	NR_033815.3		n.2561G>A		non_coding_transcript_exon	Exon 20 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2CL	ENST00000318962.9	TSL:1 MANE Select	c.2213G>A	p.Arg738His	missense	Exon 20 of 26	ENSP00000313670.4	Q60I27-1
	ALS2CL	ENST00000434140.5	TSL:1	n.*891G>A		non_coding_transcript_exon	Exon 20 of 26	ENSP00000405335.1	G5E9N5
	ALS2CL	ENST00000434140.5	TSL:1	n.*891G>A		3_prime_UTR	Exon 20 of 26	ENSP00000405335.1	G5E9N5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251124 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000616

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1461468 Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54 AN XY: 727064

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111988

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74458

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.34
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.065
Sift	Benign	0.12	T
Sift4G	Benign	0.081	T
Polyphen		0.080	B
Vest4		0.17
MVP		0.040
MPC		0.15
ClinPred		0.019	T
GERP RS		0.88
Varity_R		0.031
gMVP		0.094
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs554056115; hg19: chr3-46717150; COSMIC: COSV100015035; COSMIC: COSV100015035;