3-46675660-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147129.5(ALS2CL):​c.2213G>T​(p.Arg738Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R738H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2CL NM_147129.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2413446).

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>T	p.Arg738Leu	missense	Exon 20 of 26	NP_667340.2
	ALS2CL	NM_001190707.2		c.2213G>T	p.Arg738Leu	missense	Exon 20 of 26	NP_001177636.1	Q60I27-1
	ALS2CL	NR_033815.3		n.2561G>T		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>T	p.Arg738Leu	missense	Exon 20 of 26	ENSP00000313670.4	Q60I27-1
	ALS2CL	ENST00000434140.5	TSL:1	n.*891G>T		non_coding_transcript_exon	Exon 20 of 26	ENSP00000405335.1	G5E9N5
	ALS2CL	ENST00000434140.5	TSL:1	n.*891G>T		3_prime_UTR	Exon 20 of 26	ENSP00000405335.1	G5E9N5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.34
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.094
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.013	D
Polyphen		0.84	P
Vest4		0.43
MutPred		0.43		Loss of glycosylation at K739 (P = 0.044)
MVP		0.23
MPC		0.20
ClinPred		0.65	D
GERP RS		0.88
Varity_R		0.12
gMVP		0.18
Mutation Taster		=90/10	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: COSV59674084; COSMIC: COSV59674084;