rs3219161

chr2-201728557-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020919.4(ALS2):c.2796C>T(p.Ser932=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,613,840 control chromosomes in the GnomAD database, including 8,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (647 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7444 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.943

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-201728557-G-A is Benign according to our data. Variant chr2-201728557-G-A is described in ClinVar as [Benign]. Clinvar id is 261369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201728557-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.943 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.2796C>T	p.Ser932=	synonymous_variant	15/34	ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.2796C>T	p.Ser932=	synonymous_variant	15/34	1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13175 AN: 152010 Hom.: 646 Cov.: 32

Gnomad AFR AF: 0.0666

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0516

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0888

Gnomad OTH AF: 0.0798

GnomAD3 exomes AF: 0.0959 AC: 23921 AN: 249356 Hom.: 1429 AF XY: 0.0991 AC XY: 13412 AN XY: 135304

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.0870

Gnomad OTH exome AF: 0.0887

GnomAD4 exome AF: 0.0951 AC: 138997 AN: 1461712 Hom.: 7444 Cov.: 32 AF XY: 0.0960 AC XY: 69793 AN XY: 727156

Gnomad4 AFR exome AF: 0.0675

Gnomad4 AMR exome AF: 0.0378

Gnomad4 ASJ exome AF: 0.0779

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.0974

Gnomad4 NFE exome AF: 0.0902

Gnomad4 OTH exome AF: 0.0974

GnomAD4 genome AF: 0.0866 AC: 13180 AN: 152128 Hom.: 647 Cov.: 32 AF XY: 0.0893 AC XY: 6642 AN XY: 74364

Gnomad4 AFR AF: 0.0667

Gnomad4 AMR AF: 0.0514

Gnomad4 ASJ AF: 0.0698

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0888

Gnomad4 OTH AF: 0.0790

Alfa AF: 0.0842 Hom.: 317

Bravo AF: 0.0819

Asia WGS AF: 0.181 AC: 629 AN: 3478

EpiCase AF: 0.0875

EpiControl AF: 0.0833

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Infantile-onset ascending hereditary spastic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Amyotrophic lateral sclerosis type 2, juvenile Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ALS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	13
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3219161; hg19: chr2-202593280; COSMIC: COSV51887461; COSMIC: COSV51887461;