chr3-46676873-G-A

Position:

• chr3-46676873-G-A

Variant summary

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

The NM_147129.5(ALS2CL):​c.1907C>T​(p.Ser636Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,448 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2CL	NM_147129.5	c.1907C>T	p.Ser636Phe	missense_variant	17/26	ENST00000318962.9
ALS2CL	NM_001190707.2	c.1907C>T	p.Ser636Phe	missense_variant	17/26
ALS2CL	NR_033815.3	n.1965C>T		non_coding_transcript_exon_variant	17/26
ALS2CL	NR_135622.2	n.1965C>T		non_coding_transcript_exon_variant	17/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2CL	ENST00000318962.9	c.1907C>T	p.Ser636Phe	missense_variant	17/26	1	NM_147129.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461448 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jan 09, 2024

The c.1907C>T (p.S636F) alteration is located in exon 17 (coding exon 16) of the ALS2CL gene. This alteration results from a C to T substitution at nucleotide position 1907, causing the serine (S) at amino acid position 636 to be replaced by a phenylalanine (F). 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	0.17
BayesDel_addAF	Benign	-0.0071	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.25
Sift	Benign	0.066	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.72
MutPred		0.39		Gain of glycosylation at S636 (P = 0.003);Gain of glycosylation at S636 (P = 0.003);
MVP		0.51
MPC		0.52
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr3-46718363;