2-201702041-C-A

Variant names:

• chr2-201702041-C-A
• rs3731707
• NM_020919.4:c.4936-152G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020919.4(ALS2):​c.4936-152G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 572,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139
• Publications: 8 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4936-152G>T		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.4933-152G>T		intron	N/A	NP_001397904.1	A0A7P0T8F3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.4936-152G>T		intron	N/A	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680000.1		c.*2060G>T		3_prime_UTR	Exon 33 of 33	ENSP00000506173.1	A0A7P0Z4J9
	ALS2	ENST00000680497.1		c.5038-152G>T		intron	N/A	ENSP00000505954.1	A0A7P0Z4F3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000698 AC: 4 AN: 572992 Hom.: 0 AF XY: 0.00000330 AC XY: 1 AN XY: 302822

African (AFR) AF: 0.00 AC: 0 AN: 15394

American (AMR) AF: 0.00 AC: 0 AN: 31382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17706

East Asian (EAS) AF: 0.00 AC: 0 AN: 30956

South Asian (SAS) AF: 0.00 AC: 0 AN: 53694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2216

European-Non Finnish (NFE) AF: 0.0000115 AC: 4 AN: 348294

Other (OTH) AF: 0.00 AC: 0 AN: 29746

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 7297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.6
DANN	Benign	0.74
PhyloP100		-0.14

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: rs3731707; hg19: chr2-202566764;