chr2-201733377-T-A
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_020919.4(ALS2):c.2479A>T(p.Thr827Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,613,640 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T827A) has been classified as Uncertain significance.
Frequency
Consequence
NM_020919.4 missense
Scores
Clinical Significance
Conservation
Publications
- ALS2-related motor neuron diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- amyotrophic lateral sclerosis type 2, juvenileInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- infantile-onset ascending hereditary spastic paralysisInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
- juvenile primary lateral sclerosisInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- juvenile amyotrophic lateral sclerosisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000552 AC: 84AN: 152172Hom.: 1 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000489 AC: 122AN: 249290 AF XY: 0.000525 show subpopulations
GnomAD4 exome AF: 0.000377 AC: 551AN: 1461468Hom.: 1 Cov.: 30 AF XY: 0.000432 AC XY: 314AN XY: 727042 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000552 AC: 84AN: 152172Hom.: 1 Cov.: 33 AF XY: 0.000646 AC XY: 48AN XY: 74328 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 2, juvenile Pathogenic:1Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This variant was classified as: Likely pathogenic. -
not specified Benign:2
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not provided Benign:2
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Peripheral axonal neuropathy Pathogenic:1
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ALS2-related disorder Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hereditary spastic paraplegia Uncertain:1
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Tip-toe gait Uncertain:1
Gait disorder -
Infantile-onset ascending hereditary spastic paralysis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at