NM_020919.4:c.4004+25C>T

Variant names:

• chr2-201715647-G-A
• rs3219167
• NM_020919.4:c.4004+25C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.4004+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,613,194 control chromosomes in the GnomAD database, including 556,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50739 hom., cov: 32)
  • Exomes 𝑓: 0.83 (505829 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.859
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-201715647-G-A is Benign according to our data. Variant chr2-201715647-G-A is described in ClinVar as Benign. ClinVar VariationId is 261375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4004+25C>T		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.4001+25C>T		intron	N/A	NP_001397904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.4004+25C>T		intron	N/A	ENSP00000264276.6
	ALS2	ENST00000680497.1		c.4106+25C>T		intron	N/A	ENSP00000505954.1
	ALS2	ENST00000679516.1		c.4004+25C>T		intron	N/A	ENSP00000505187.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124110 AN: 152064 Hom.: 50695 Cov.: 32

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.831 AC: 205194 AN: 246858 AF XY: 0.833

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.832

GnomAD4 exome AF: 0.832 AC: 1214904 AN: 1461012 Hom.: 505829 Cov.: 41 AF XY: 0.832 AC XY: 605058 AN XY: 726826

African (AFR) AF: 0.785 AC: 26257 AN: 33466

American (AMR) AF: 0.853 AC: 38129 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 21856 AN: 26126

East Asian (EAS) AF: 0.748 AC: 29704 AN: 39686

South Asian (SAS) AF: 0.842 AC: 72591 AN: 86224

European-Finnish (FIN) AF: 0.854 AC: 45626 AN: 53412

Middle Eastern (MID) AF: 0.818 AC: 4716 AN: 5768

European-Non Finnish (NFE) AF: 0.833 AC: 926068 AN: 1111260

Other (OTH) AF: 0.828 AC: 49957 AN: 60356

GnomAD4 genome AF: 0.816 AC: 124209 AN: 152182 Hom.: 50739 Cov.: 32 AF XY: 0.817 AC XY: 60810 AN XY: 74410

African (AFR) AF: 0.780 AC: 32358 AN: 41496

American (AMR) AF: 0.834 AC: 12758 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2930 AN: 3472

East Asian (EAS) AF: 0.747 AC: 3869 AN: 5178

South Asian (SAS) AF: 0.841 AC: 4054 AN: 4822

European-Finnish (FIN) AF: 0.856 AC: 9078 AN: 10600

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56495 AN: 68002

Other (OTH) AF: 0.808 AC: 1707 AN: 2112

Alfa AF: 0.830 Hom.: 69798

Bravo AF: 0.812

Asia WGS AF: 0.788 AC: 2739 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)
-	-	1	Infantile-onset ascending hereditary spastic paralysis (1)
-	-	1	Juvenile primary lateral sclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.45
DANN	Benign	0.50
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3219167; hg19: chr2-202580370;