rs199751225
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1
The NM_020919.4(ALS2):āc.4964A>Cā(p.Lys1655Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00043 ( 1 hom., cov: 32)
Exomes š: 0.000055 ( 0 hom. )
Consequence
ALS2
NM_020919.4 missense
NM_020919.4 missense
Scores
4
4
11
Clinical Significance
Conservation
PhyloP100: 7.60
Genes affected
ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.09196958).
BP6
?
Variant 2-201701861-T-G is Benign according to our data. Variant chr2-201701861-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446823.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000434 (66/152180) while in subpopulation AFR AF= 0.00147 (61/41512). AF 95% confidence interval is 0.00117. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.4964A>C | p.Lys1655Thr | missense_variant | 34/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.4964A>C | p.Lys1655Thr | missense_variant | 34/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000427 AC: 65AN: 152062Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000105 AC: 26AN: 248180Hom.: 0 AF XY: 0.0000965 AC XY: 13AN XY: 134744
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GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461614Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 727110
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GnomAD4 genome ? AF: 0.000434 AC: 66AN: 152180Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74396
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 30, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2021 | The c.4964A>C (p.K1655T) alteration is located in exon 34 (coding exon 33) of the ALS2 gene. This alteration results from a A to C substitution at nucleotide position 4964, causing the lysine (K) at amino acid position 1655 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Infantile-onset ascending hereditary spastic paralysis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at