3-46676671-G-A

Position:

• chr3-46676671-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147129.5(ALS2CL):​c.1999C>T​(p.Pro667Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2CL NM_147129.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080450505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2CL	NM_147129.5	c.1999C>T	p.Pro667Ser	missense_variant	18/26	ENST00000318962.9
ALS2CL	NM_001190707.2	c.1999C>T	p.Pro667Ser	missense_variant	18/26
ALS2CL	NR_033815.3	n.2057C>T		non_coding_transcript_exon_variant	18/26
ALS2CL	NR_135622.2	n.2057C>T		non_coding_transcript_exon_variant	18/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2CL	ENST00000318962.9	c.1999C>T	p.Pro667Ser	missense_variant	18/26	1	NM_147129.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.1999C>T (p.P667S) alteration is located in exon 18 (coding exon 17) of the ALS2CL gene. This alteration results from a C to T substitution at nucleotide position 1999, causing the proline (P) at amino acid position 667 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.43
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.082
Sift	Benign	0.22	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0010	B;B
Vest4		0.27
MutPred		0.39		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.24
MPC		0.12
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.078
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46718161;