2-201741858-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_020919.4(ALS2):c.2171-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ALS2
NM_020919.4 splice_region, intron

Scores

Splicing: ADA: 0.0001528

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.105

Publications

0 publications found

Variant links:

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]

ALS2 Gene-Disease associations (from GenCC):

ALS2-related motor neuron disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
amyotrophic lateral sclerosis type 2, juvenile
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
infantile-onset ascending hereditary spastic paralysis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
juvenile primary lateral sclerosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 2-201741858-T-C is Benign according to our data. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-201741858-T-C is described in CliVar as Likely_benign. Clinvar id is 465185.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.2171-4A>G		splice_region_variant, intron_variant	Intron 10 of 33	ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 link	c.2171-4A>G		splice_region_variant, intron_variant	Intron 10 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247080

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457110

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1108130

Other (OTH)

AF:

0.0000166

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Aug 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.5

(source)

DANN

Benign

0.74

PhyloP100

-0.10

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.0080

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over