chr2-201726434-C-T

Variant names:

• chr2-201726434-C-T
• rs143317076
• NM_020919.4:c.3248+50G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020919.4(ALS2):​c.3248+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,468,126 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.017 (243 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.106
• Publications: 1 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=-0.93).
• BP6: Variant 2-201726434-C-T is Benign according to our data. Variant chr2-201726434-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2066/152260) while in subpopulation NFE AF = 0.0184 (1252/68024). AF 95% confidence interval is 0.0176. There are 24 homozygotes in GnomAd4. There are 1034 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.3248+50G>A		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.3248+50G>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.3248+50G>A		intron	N/A	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000482891.6	TSL:1	n.4016+50G>A		intron	N/A
	ALS2	ENST00000680497.1		c.3350+50G>A		intron	N/A	ENSP00000505954.1	A0A7P0Z4F3

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2069 AN: 152142 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0156 AC: 3871 AN: 248548 AF XY: 0.0158

Gnomad AFR exome AF: 0.00311

Gnomad AMR exome AF: 0.00920

Gnomad ASJ exome AF: 0.0404

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0172 AC: 22693 AN: 1315866 Hom.: 243 Cov.: 20 AF XY: 0.0171 AC XY: 11336 AN XY: 662728

African (AFR) AF: 0.00322 AC: 98 AN: 30412

American (AMR) AF: 0.00921 AC: 410 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 988 AN: 25310

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38958

South Asian (SAS) AF: 0.00505 AC: 420 AN: 83198

European-Finnish (FIN) AF: 0.0238 AC: 1254 AN: 52704

Middle Eastern (MID) AF: 0.0271 AC: 150 AN: 5532

European-Non Finnish (NFE) AF: 0.0189 AC: 18476 AN: 979726

Other (OTH) AF: 0.0161 AC: 896 AN: 55514

GnomAD4 genome AF: 0.0136 AC: 2066 AN: 152260 Hom.: 24 Cov.: 32 AF XY: 0.0139 AC XY: 1034 AN XY: 74452

African (AFR) AF: 0.00381 AC: 158 AN: 41522

American (AMR) AF: 0.0103 AC: 158 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.0216 AC: 229 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0184 AC: 1252 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0115 Hom.: 4

Bravo AF: 0.0130

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.3
DANN	Benign	0.68
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs143317076; hg19: chr2-202591157;