rs3731707

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-201702041-C-T
• chr2-201702041-C-A

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.4936-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 720,062 control chromosomes in the GnomAD database, including 33,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6372 hom., cov: 25)
  • Exomes 𝑓: 0.28 (26786 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-201702041-C-T is Benign according to our data. Variant chr2-201702041-C-T is described in ClinVar as Benign. ClinVar VariationId is 1230069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4936-152G>A		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.4933-152G>A		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>A		intron	N/A	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680000.1		c.*2060G>A		3_prime_UTR	Exon 33 of 33	ENSP00000506173.1	A0A7P0Z4J9
	ALS2	ENST00000680497.1		c.5038-152G>A		intron	N/A	ENSP00000505954.1	A0A7P0Z4F3

Frequencies

GnomAD3 genomes AF: 0.278 AC: 41242 AN: 148360 Hom.: 6360 Cov.: 25

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.278 AC: 158666 AN: 571584 Hom.: 26786 AF XY: 0.286 AC XY: 86308 AN XY: 302060

African (AFR) AF: 0.315 AC: 4832 AN: 15346

American (AMR) AF: 0.181 AC: 5680 AN: 31304

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 4765 AN: 17658

East Asian (EAS) AF: 0.638 AC: 19699 AN: 30900

South Asian (SAS) AF: 0.462 AC: 24726 AN: 53536

European-Finnish (FIN) AF: 0.313 AC: 13595 AN: 43492

Middle Eastern (MID) AF: 0.253 AC: 560 AN: 2216

European-Non Finnish (NFE) AF: 0.220 AC: 76491 AN: 347452

Other (OTH) AF: 0.280 AC: 8318 AN: 29680

GnomAD4 genome AF: 0.278 AC: 41298 AN: 148478 Hom.: 6372 Cov.: 25 AF XY: 0.286 AC XY: 20651 AN XY: 72162

African (AFR) AF: 0.314 AC: 12576 AN: 40088

American (AMR) AF: 0.190 AC: 2790 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 918 AN: 3454

East Asian (EAS) AF: 0.628 AC: 3175 AN: 5054

South Asian (SAS) AF: 0.488 AC: 2220 AN: 4546

European-Finnish (FIN) AF: 0.332 AC: 3335 AN: 10040

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15439 AN: 67400

Other (OTH) AF: 0.268 AC: 545 AN: 2036

Alfa AF: 0.234 Hom.: 7297

Bravo AF: 0.268

Asia WGS AF: 0.569 AC: 1975 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.9
DANN	Benign	0.74
PhyloP100		-0.14
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: rs3731707; hg19: chr2-202566764;